rnest R. Anderson, Jr, MS,
RPh, who became president
of the Association of Community Cancer Centers (ACCC) at
its 34th annual meeting last April, is
the first pharmacist to serve in this
position. Previously, he was the first
pharmacist on ACCC’s Board of
Directors and helped establish the
Oncology Pharmacy Education Network (OPEN) within the organization. Anderson is director of pharma-

™

cy at the Lahey Clinic, Burlington,
Mass., and the Lahey Clinic North in
Peabody, Mass. Anderson is also associate clinical professor of pharmacy at
Northeastern University College of
Pharmacy and Allied Health Profession and adjunct associate professor
of pharmacy at Massachusetts
College of Pharmacy and Health
Sciences in Boston. The Oncology
Pharmacist recently spoke with him
about his views on the role of phar-

macists in oncology practice and what he hopes to accomplish
in his term as ACCC president.

Please tell us about your
education and training and
how you got into oncology
pharmacy.
My present position is director of
pharmacy at the Lahey Clinic. I’ve

H

ealthcare payers are seeking greater control
over the billions of dollars spent in treating
cancer. The focus of their effort is pharmaceuticals, the escalating cost of which—thanks to advances
in biotechnology—was unfathomable a decade ago.
Specialty pharmacies emerged as a way to save cost and
monitor patient compliance and safety in other disease
states—initially, hemophilia. These entities brought a
degree of expertise regarding niche drugs, and offered a
Continued on page 14

Complimentary CE Credit

Continued on page 10

SKIN CANCERS

SAFE HANDLING

Advanced Melanoma
Targeted by Newer
Molecular Therapies

Work Surface Sampling Reveals
High Rates of Drug
Contamination

ANAHEIM—Molecular pathways involved in the
pathogenesis of malignant melanoma are the targets of
an emerging group of therapies that may revolutionize
the treatment of this disease, said Jamie Poust,
PharmD, University of Colorado Hospital, Aurora.
In the United States, melanoma is the most common

ANAHEIM—A large-scale study of the feasibility of
antineoplastic drug contamination testing by wipe sample monitoring has revealed high levels of drug contamination on work benches, refrigerator doors, and
other surfaces in multiple pharmacies.
The findings, reported in a poster session at the 2008
Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners

Continued on page 26

Continued on page 18

Program #CIK9976:
Finasteride and Prostate
Cancer Prevention:
The Latest Chapter

Common Pain Relievers May Affect Prostate Cancer Biomarker
Men with prostate cancer should be alerted that common pain
killers such as aspirin and ibuprofen may affect their prostate-specific antigen (PSA) levels and could artificially mask their risk of
prostate cancer.
“More than anything, these findings
underscore the importance for doctors to
know what medications their patients are
on,” said study investigator Eric Singer, MD,
who is a urology resident at the University
of Rochester Medical Center, New York.
“We showed that men who regularly took
certain medications like aspirin and other
nonsteroidal anti-inflammatory drugs
(NSAIDs) had a lower serum PSA level.”
Singer’s team studied the records of 1319
men older than 40 years of age who took part
in the 2001-2002 National Health and
Nutrition Examination Survey (NHANES).
The team looked at the men’s use of NSAIDs and the painkiller
acetaminophen and their PSA levels. The investigators found men
who used NSAIDs regularly had PSA levels about 10% lower than
men who did not. The results were similar with acetaminophen, but

Researchers in Germany
The German researchers found that methadone was as effective as
have discovered that metha- standard chemotherapies and radiation treatments against nonresisdone has surprising killing tant leukemia cells and that nonleukemic peripheral blood lymphopower against leukemia cells. cytes survived after methadone treatment. To their surprise, they also
They have just published a found that methadone effectively killed leukemia cells that were
study that suggests methadone resistant to multiple chemotherapies and to radiation.
holds promise as a new therapy
Probing the mechanism of methadone’s action, the researchers
for leukemia, especially in found that it activates the mitochondrial pathway within leukemia
patients whose cancer no cells, which activates enzymes called caspases that prompt a cell into
longer responds to chemother- apoptosis. Chemotherapy agents use the same approach, but
apy and radiation (Friesen C, methadone activated caspases in sensitive leukemia cells and also
et al. Cancer Res. 2008;68: reversed deficient activation of caspases in resistant leukemia cells.
6059-6064).
In this study, the single doses used to kill leukemia cells were
“Methadone kills sensitive greater than the doses used to treat opioid addiction, but the
leukemia cells and also breaks treatment resistance, but without any researchers have since found that they can use a daily low dose of
toxic effects on nonleukemic blood cells,” said study senior author methadone to achieve the same effect. Friesen notes that while
Claudia Friesen, PhD, a research scientist at the Institute of Legal methadone may become addictive, it is much easier to break
Medicine at the University of Ulm, Germany. “We find this very methadone addiction than true opioid addiction. “Addiction should
exciting, because once conventional treatments have failed, which not be an unsolvable problem if methadone is ever used as an antioccurs in old and also in young patients, they have no other options.” cancer therapy,” she said.
Methadone, developed in
Germany in the 1930s, is a lowcost agent that acts on opioid
Novel Drug May Help Prevent
receptors, and is used as an opioid substitute to treat addiction.
Chemotherapy-Induced Hearing Loss
Scientists have found that opiResearchers at the Oregon Health and carboplatin-induced hearing loss was widely
oid receptors also exist on the
Science University in Portland are testing a underestimated because of inadequate testing or
surface of some cancer cells for
promising new agent to prevent chemothera- a lack of reporting.
reasons that are not fully underpy-induced hearing loss in patients with
In several preclinical studies, researchers
stood. One research group testadvanced head and neck and non–small-cell found that a novel chemoprotectant drug proded the agent in human lung
lung cancer.
uct being developed by Sound
cancer cells lines and found that
Hearing loss due to ototoxic medPharmaceuticals in Seattle, Wash.
it can induce cell death.
ications such as chemotherapy,
helps prevent ototoxicity while
In this study, Friesen and her
antibiotics, or loop diuretics often
not interfering with the chemocolleagues tested methadone
results in permanent and progrestherapy treatment. The drug,
in leukemia cells in laboratory
sive disability. Furthermore, the
which is a small molecule that
culture because this cancer
combined use of these ototoxic
mimics and induces glutathione
also expresses the opioid recepagents is contraindicated, often limperoxidase activity, is being tested
tor. This is the first study to
iting their clinical utility. Symptoms
in a phase 2 trial that includes 80
look at use of this agent in
of ototoxicity include hearing loss,
cancer patients. In one animal
leukemia, specifically in lymtinnitus, dizziness, vertigo, and diffistudy, this agent was also found to
phoblastic leukemia T-cell
culty understanding speech. Historienhance the tumoricidal activity
lines and human myeloid
cally, the incidence of cisplatin- or
of cisplatin.
leukemia cell lines.

…making today’s therapies more accessible and
tomorrow’s breakthroughs more achievable
Supporting today
The Genentech® Access to Care Foundation makes our
marketed products available to qualified patients in need*
Genentech BioOncology™ Access Solutions™, formerly known as
SPOC® (Single Point of Contact)
— For patients and their healthcare providers, Genentech BioOncology
Access Solutions provides coverage and reimbursement support,
patient assistance, and informational resources
Investing in tomorrow
Genentech BioOncology invests deeply in research and development
and is an industry leader in investing a percentage of annual
revenues back into R&D
Genentech BioOncology funds grant and fellowship programs
to support medical education, partner with professional societies,
and encourage independent research
*The Genentech Access to Care Foundation was established to help qualified patients with unmet medical
needs who are uninsured or rendered uninsured by payer denial and who meet specific medical criteria
to receive proper medical treatment. The Genentech Access to Care Foundation may be available to help
those who are not able to obtain Genentech therapeutics for financial reasons.

he election of my friend and colleague Ernest R. Anderson as
president of the multidisciplinary Association of Community
Cancer Centers (ACCC) this year says a lot about the status
of oncology pharmacy as a specialty. Oncology pharmacists have an
organization of our own—the Hematology/Oncology Pharmacy
Association. But we also need to work closely with physicians, nurses, and other healthcare professionals, and Anderson’s election signifies the increasingly central role pharmacists now play in cancer
care. Anderson believes that pharmacists working together with
other healthcare professionals can be a strong voice in healthcare
policy making, and he emphasizes the importance of leadership skills
to be effective as clinicians, administrators, and as advocates for our
profession and our patients.
One issue that has generated considerable debate is the role of
oncology specialty pharmacies. The article entitled “The ‘Growing
Pains’ of Oncology Specialty Pharmacy” explores this issue, presenting the views of representatives of specialty pharmacies, healthcare
management and consulting firms, and insurance companies on the
need for and value of these pharmacies.
The continuing education article this month raises interesting
questions about risks versus benefits of prostate cancer chemoprevention. Initial results of the large Prostate Cancer Prevention Trial
(PCPT), which were reported in 2003, showed that treatment with
finasteride significantly reduced the risk of prostate cancer but with

Coming
Soon
CE article:
Quality of Life in Metastatic Renal Cell Carcinoma
Setting Up a Chemotherapy Prep Area
in a Community Practice
Using Nanoparticles to Deliver Chemotherapy
New Technologies in HER2 Testing

an apparent increase in the risk of high-grade disease. A new analysis of the PCPT data indicates that this concern was unfounded and
suggests the drug be offered as an option for men concerned about
the risk of prostate cancer. The new analysis received much media
attention, so it is important for oncology pharmacists to be prepared
to answer patients’ questions about the potential use of finasteride or
other measures for prostate cancer prevention.
The Practical Applications review on management of venous
thromboembolism (VTE) addresses another major issue in oncology
practice. In September, the Acting Surgeon General issued a Call to
Action to reduce the incidence of deep vein thrombosis and pulmonary embolism in the United States. VTE is of particular concern
to patients with cancer because it is a frequent complication in this
population and adversely affects prognosis and quality of life. With
the introduction of the low-molecular-weight heparins, clinicians
now have a new option for preventing and treating VTE.
One way oncology pharmacists can have a say in public health
issues is government service. The article on careers with the US
Food and Drug Administration provides detailed information on the
types of jobs available within that agency for pharmacy students and
graduates.
If you would like to share your views on these and other important issues affecting oncology practice, please write to Karen@
greenhillhc.com.

Protection that’s easy to use.
Designed with a few simple steps
for minimal changes to your
current practice.

NEW ONGUARD™ Contained
Medication System enables
safe and easy handling of
hazardous medications.

Protection you can hear and feel.
The unique design of the ONGUARD™
System allows you to hear and feel
that connections are secure.

Protection you can depend on.
Be protected from vapors, particles
and aerosols. Even at disconnection,
components are sealed and dry.
And non-sterile air never enters
the medication vial.
Call for a demo today.
To see the ONGUARD™ System in
action, call B. Braun to schedule a
demonstration at 800-227-2862,
or visit www.bbraunusa.com.

■ HPV
Researcher
Receives Nobel
Prize in
Physiology and
Medicine
German virologist
Dr Harald zur Hausen
has been awarded the
2008 Nobel Prize in
Physiology and Medicine for his discovery that certain types of human
papillomavirus (HPV) cause cervical
cancer. He shares the prize with French
virologists Dr Françoise Barré-Sinoussi
and Dr Luc Montagnier, who discovered the human immunodeficiency
virus, which causes AIDS. Dr zur
Hausen’s research contributed to the
development of vaccines that protect
against cervical cancer.
■ Chemotherapy May Delay
Need for Radiation in Children
with Brain Tumors
Using chemotherapy alone and
delaying or even avoiding radiation
may be an effective alternative approach for children with unresectable
or progressive low-grade glioma, a
Children’s Oncology Group study suggests. The results of the multi-institutional study “confirmed the ability of
chemotherapy to control the disease,”
said Joann Ater, MD, professor of pediatrics at the Children’s Cancer
Hospital at M.D. Anderson Cancer
Center, Houston, Tex., speaking at the
40th Annual International Society of
Pediatric Oncology meeting in Berlin,
Germany. The 401 patients enrolled in
the trial were treated with one of two
different chemotherapy regimens—
carboplatin and vincristine (CV) or
thioguanine, procarbazine, lomustine,
and vincristine (TPCV). The TPCV
regimen was more effective than the
CV regimen and resulted in a 5-year
event-free survival rate of nearly 50%.
“If we can delay radiation, then we can
allow more time for our youngest pa-

peutic Radiology and Oncology. Medicare HMOs cover the 20% difference
between Medicare reimbursement and
the cost of care, but patients who enroll
in “qualifying” clinical trials lose that
extra coverage. This could increase
their out-of-pocket costs by as much as
$3000 a month, Lin and colleagues
found in a study of patients with new
cancer diagnoses treated at five
Pennsylvania hospitals. In 2007, 103
cancer patients screened for clinical trials at these cancer centers declined to
participate because of costs, the re-

■ Survival Increasing for
Children with Hematologic
Malignancies
Five- and 10-year survival rates continue to increase for US children diagnosed with three of the most common
childhood hematologic malignancies—
acute lymphoblastic leukemia (ALL),
acute nonlymphoblastic leukemia, and
non-Hodgkin’s lymphoma (NHL)—a

new report shows. Hermann Brenner,
MD, of the German Cancer Research
Center in Heidelberg and his colleagues found that between 1990-1994
and 2000-2004, 5- and 10-year survival
increased from 80.2% to 87.5% and
from 73.4% to 83.8%, respectively, for
children 15 years of age or younger with
ALL; from 41.9% to 59.9% and from
38.7% to 59.1%, respectively, for those
with acute nonlymphoblastic leukemia;
and from 76.6% to 87.7% and from
73.0% to 86.9%, respectively, for those
with NHL. Survival rates for children

CONTROL
THE RESPONSE
MANAGE HEMOGLOBIN
AND REDUCE TRANSFUSIONS
When Treating Your Patients:
• Evaluate for other treatable etiologies of anemia (iron, folate, or B12
deﬁciency, hemolysis, or bleeding) to treat appropriately
• PROCRIT therapy should not be initiated at hemoglobin (Hb) levels 10 g/dL
• The dose of PROCRIT should be titrated for each patient to achieve and maintain
the lowest Hb level sufﬁcient to avoid the need for red blood cell (RBC) transfusion
• The rate of Hb increase should not exceed 1 g/dL in any 2-week period
• Monitor Hb weekly until stable, and then regularly during therapy

If we can delay radiation,
then we can allow
more time for our
youngest patients to
develop physically.

NEWS NOTES

tients to develop physically, which
could decrease some of the long-term
effects from treatment,” Ater said in a
press release. Long-term effects of radiation include mental impairment, hormonal deficiencies, and increased rate
of stroke late in life, causing some
physicians and families to avoid radiation treatment.

■ Medicare HMO Rules May Be
Barrier to Clinical Trial
Participation
Enrollment in a Medicare HMO may
limit the number of older people participating in clinical trials, said Chyongchiou Lin, PhD, at the annual meeting
of the American Society for Thera6

G REEN H ILL H EALTHCARE C OMMUNICATIONS

November/December 2008

■ New Website Matches Breast
Cancer Patients with Trials
Information on breast cancer clinical
trials taking place at more than 1100
medical facilities nationwide is available

on a website recently launched by the
University of California, San Francisco
Center of Excellence for Breast Cancer
Care. BreastCancerTrials.org, a free,
nonprofit, clinical trials matching service, matches patients with or at risk for
breast cancer with trials that are specific
to their personal health situation. The
site provides contact information for the
trial and criteria for enrollment.
Individuals can use the website on a
one-time basis or store their health history on secure servers for continual
matching to newly listed trials.

■ Alison Martin, MD, to Head
Melanoma Research Alliance
Alison Martin, MD, has been named

PROCRIT Indication

Additional Important Safety Information

PROCRIT is indicated for the treatment of anemia due to the effect of
concomitantly administered chemotherapy based on studies that have
shown a reduction in the need for RBC transfusions in patients with
metastatic, non-myeloid malignancies receiving chemotherapy for
a minimum of 2 months. Studies to determine whether PROCRIT
increases mortality or decreases progression-free/recurrence-free
survival are ongoing.
• PROCRIT is not indicated for use in patients receiving hormonal
agents, therapeutic biologic products, or radiotherapy unless receiving
concomitant myelosuppressive chemotherapy.
• PROCRIT is not indicated for patients receiving myelosuppressive
therapy when the anticipated outcome is cure due to the absence
of studies that adequately characterize the impact of PROCRIT on
progression-free and overall survival (see WARNINGS: Increased
Mortality and/or Increased Risk of Tumor Progression or Recurrence).
• PROCRIT is not indicated for the treatment of anemia in cancer
patients due to other factors such as iron or folate deficiencies,
hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or
Loss of Response).
• PROCRIT use has not been demonstrated in controlled clinical
trials to improve symptoms of anemia, quality of life, fatigue, or
patient well-being.

• Patients with chronic renal failure experienced greater risks for death
and serious cardiovascular events (including myocardial infarction,
stroke, congestive heart failure, and hemodialysis vascular access
thrombosis) when administered ESAs to target higher versus lower
hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical
studies; these risks also increased in controlled clinical trials of
patients with cancer. A rate of hemoglobin rise of >1 g/dL over
2 weeks may contribute to these risks.
• PROCRIT therapy should not be initiated at hemoglobin levels
10 g/dL.
• The dose of PROCRIT should be titrated for each patient to achieve
and maintain the lowest hemoglobin level sufﬁcient to avoid the need
for blood transfusion.
• When the hemoglobin reaches a level needed to avoid transfusion
or, increases by more than 1 g/dL in a 2-week period, the PROCRIT
dose should be reduced by 25%. Withhold the dose of PROCRIT if the
hemoglobin exceeds a level needed to avoid transfusion. Restart dose
at 25% below the previous dose when the hemoglobin approaches a
level where transfusions may be required. Discontinue if after 8 weeks
of therapy there is no response as measured by hemoglobin levels or
if transfusions are still required.
• Monitor hemoglobin regularly during therapy, weekly until hemoglobin
becomes stable.
• Cases of pure red cell aplasia (PRCA) and of severe anemia, with or
without other cytopenias, associated with neutralizing antibodies to
erythropoietin have been reported in patients treated with PROCRIT;
predominantly in patients with chronic renal failure receiving PROCRIT
by subcutaneous administration. If any patient develops a sudden loss
of response to PROCRIT, accompanied by severe anemia and low
reticulocyte count, and anti-erythropoietin antibody-associated anemia
is suspected, withhold PROCRIT and other erythropoietic proteins.
Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624)
to perform assays for binding and neutralizing antibodies. If
erythropoietin antibody-mediated anemia is confirmed, PROCRIT
should be permanently discontinued and patients should not be
switched to other erythropoietic proteins.
• The safety and efﬁcacy of PROCRIT therapy have not been established
in patients with a known history of a seizure disorder or underlying
hematologic disease (e.g., sickle cell anemia, myelodysplastic
syndromes, or hypercoagulable disorders).
• In some female patients, menses have resumed following PROCRIT
therapy; the possibility of pregnancy should be discussed and the
need for contraception evaluated.
• Prior to and regularly during PROCRIT therapy monitor iron status;
transferrin saturation should be 20% and ferritin should be
100 ng/mL. During therapy absolute or functional iron deficiency
may develop and all patients will eventually require supplemental
iron to adequately support erythropoiesis stimulated by PROCRIT.
• Treatment of patients with grossly elevated serum erythropoietin
levels (e.g., >200 mUnits/mL) is not recommended.
• During PROCRIT therapy, blood pressure should be monitored carefully
and aggressively managed, particularly in patients with an underlying
history of hypertension or cardiovascular disease.
• Seizures in PROCRIT-treated patients have been reported in the
context of a signiﬁcant increase in hemoglobin from baseline; increases
in blood pressure were not always observed; and patients may have
had other underlying central nervous system pathology.
• The most commonly reported side effects (>10%) for PROCRIT in
clinical trials were pyrexia, diarrhea, nausea, vomiting, edema,
asthenia, fatigue, shortness of breath, paresthesia, and upper
respiratory infection.

Important Safety Information
WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR
and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR
PROGRESSION OR RECURRENCE
Renal failure: Patients experienced greater risks for death
and serious cardiovascular events when administered
erythropoiesis-stimulating agents (ESAs) to target higher versus
lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL)
in two clinical studies. Individualize dosing to achieve and
maintain hemoglobin levels within the range of 10 to 12 g/dL.
Cancer:
• ESAs shortened overall survival and/or increased the risk of
tumor progression or recurrence in some clinical studies in
patients with breast, non-small cell lung, head and neck,
lymphoid, and cervical cancers (see WARNINGS: Table 1).
• To decrease these risks, as well as the risk of serious
cardio- and thrombovascular events, use the lowest dose
needed to avoid red blood cell transfusion.
• Use ESAs only for treatment of anemia due to concomitant
myelosuppressive chemotherapy.
• ESAs are not indicated for patients receiving myelosuppressive
therapy when the anticipated outcome is cure.
• Discontinue following the completion of a chemotherapy course.
Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep
venous thromboses in patients not receiving prophylactic
anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications
• PROCRIT is contraindicated in patients with uncontrolled hypertension
or with known hypersensitivity to albumin (human) or mammalian
cell-derived products.

President and Chief Executive Officer of
the Melanoma Research Alliance
(MRA), an international, cross-disciplinary group of biomedical researchers
seeking better treatments and a cure for
melanoma. Martin, a medical oncologist, has held various positions within
the National Cancer Institute, most
recently as head of Genitourinary
Cancers and Melanoma Therapeutics in
the Clinical Investigations Branch of
the Cancer Therapy Evaluation Program. The MRA is a public charity
formed in 2007 under the auspices of the
Milken Institute. It recently announced
the recipients of $8 million in grants to
fund 17 innovative melanoma research
proposals worldwide.

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on adjacent page.

tients on its website (http://www.bone
andcancerfoundation.org) and in its
publications, all of which are free. Six
patient publications are now available
in print and on the website, covering
bone metastases and treatment-related
bone loss in breast, prostate, lung cancer, and myeloma as well as osteonecrosis of the jaw and vitamin D deficiency. More information about the
BCF can be obtained by phone (888862-0999) or e-mail (bcfdn@aol.com).

NEWS NOTES

with Hodgkin’s lymphoma did not
change substantially over the study
period. For children diagnosed in 20052009, the estimated survival rate was
88.0% for ALL, 63.9% for acute nonlymphoblastic leukemia, 90.6% for
NHL, and 94.3% for Hodgkin’s lymphoma. (Pulte D, et al. J Natl Cancer
Inst. 2008;100:1301-1309.)

7

BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF
ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY
PROCRIT®
(Epoetin alfa)
FOR INJECTION

FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS,
REFER TO THE PHYSICIANS’ DESK REFERENCE®
WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC
EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE
Renal failure: Patients experienced greater risks for death and serious cardiovascular events
when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower
hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize
dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.
Cancer:
• ESAs shortened overall survival and/or increased the risk of tumor progression or
recurrence in some clinical studies in patients with breast, non-small cell lung, head and
neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).
• To decrease these risks, as well as the risk of serious cardio- and thrombovascular
events, use the lowest dose needed to avoid red blood cell transfusion.
• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
• ESAs are not indicated for patients receiving myelosuppressive therapy when the
anticipated outcome is cure.
• Discontinue following the completion of a chemotherapy course.
Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not
receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.
(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events,
WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence,
INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.)
INDICATIONS AND USAGE
PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered
chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients
with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies
to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free
survival are ongoing.
• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic
products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated
outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT®
on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk
of Tumor Progression or Recurrence).
• PROCRIT ® is not indicated for the treatment of anemia in cancer patients due to other factors such
as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss
of Response).
• PROCRIT ® use has not been demonstrated in controlled clinical trials to improve symptoms of
anemia, quality of life, fatigue, or patient well-being.
CONTRAINDICATIONS
PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to
mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human).
WARNINGS
Pediatrics
Risk in Premature Infants
The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be
associated with an increased incidence of neurological and other complications in premature infants which
are sometimes fatal.
Adults
Increased Mortality, Serious Cardiovascular and Thromboembolic Events
Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events
when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin
levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an
insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and
mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious
cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial
infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of
hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.
In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing
dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin
concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke,
or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher
hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3,
95% CI: 1.0, 1.7, p = 0.03).
Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of
1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive
heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance
hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized
to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain
at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in
this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular
access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the
group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also
been observed in patients with cancer treated with erythropoietic agents.
In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939
women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa
or placebo for up to a year. This study was designed to show that survival was superior when an ESA was
administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit
between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a
higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%)
in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on KaplanMeier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group
than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and
‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion
with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or
without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67,
95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival
hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.
An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical
orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients:
Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as
the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal
surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day
of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a
higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the
Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12
patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events.
Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction
of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND
ADMINISTRATION in full Prescribing Information).
Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult
patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to
PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the
period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not
approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence
Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival
and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced
head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving
chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and
in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy
or radiotherapy (Cancer Studies 7 and 8).
Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional
Control
Adverse
Achieved
Outcome for
Hemoglobin
Hemoglobin
Primary
ESA-containing
Study / Tumor / (n)
Target
(Median Q1,Q3)
Endpoint
Arm
Chemotherapy
Cancer Study 1
Metastatic breast
12-14 g/dL
12.9 g/dL
12-month overall Decreased 12-month
cancer (n=939)
12.2, 13.3 g/dL
survival
survival
Cancer Study 2
Lymphoid
13-15 g/dL (M)
11.0 g/dL
Proportion of
Decreased overall
malignancy (n=344)
13-14 g/dL (F)
9.8, 12.1 g/dL patients achieving
survival
a hemoglobin
response
Cancer Study 3
Early breast
12.5-13 g/dL
13.1 g/dL
Relapse-free and
Decreased 3 yr.
cancer (n=733)
12.5, 13.7 g/dL
overall survival
relapse-free and
overall survival
Cancer Study 4
Cervical Cancer
12-14 g/dL
12.7 g/dL
Progression-free
Decreased 3 yr.
(n=114)
12.1, 13.3 g/dL and overall survival
progression-free
and locoregional
and overall survival
control
and locoregional
control

Decreased overall survival:
Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious
Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher
in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months
was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm
were attributed to disease progression. Investigator assessed time to tumor progression was not different
between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs.
76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in
344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29
months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as
compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in
which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active
therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL.
Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the
patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in
989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy
or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients
receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group
(8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.
Decreased progression-free survival and overall survival:
Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was
administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment.
After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93,
2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the
darbepoetin alfa-treated arm compared to the control arm.
Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460
cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive
Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study
was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients
compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs.
7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at
3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI:
0.58, 1.91). Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control
(61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).
Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer
patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and
15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter
in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days
Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin
beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
Decreased locoregional control:
Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of
the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or
radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years
was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02).
Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated
with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This
has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT® by
subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT®,
accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of
effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss
of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other
erythropoietic proteins. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays
for binding and neutralizing antibodies. PROCRIT® should be permanently discontinued in patients with
antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies
may cross-react (see ADVERSE REACTIONS: Immunogenicity).
Albumin (Human)
PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product
manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical
risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of
transmission of viral diseases or CJD have ever been identified for albumin.
PRECAUTIONS
The parenteral administration of any biologic product should be attended by appropriate precautions in case
allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient
rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic
reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information
regarding allergic reactions).
The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of
a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes,
or hypercoagulable disorders).
In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy
should be discussed and the need for contraception evaluated.
Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with
PROCRIT®. However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in
normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should
be used with caution in patients with known porphyria.
In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with
subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may
be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis
was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19
months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not
been treated with PROCRIT®.
Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and
measured periodically thereafter.
Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the
recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency:
Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying
infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases
(ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid
or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia
(PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient
should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to
erythropoietin (see WARNINGS: Pure Red Cell Aplasia).
Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional
iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability
to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be
at least 20% and ferritin should be at least 100 ng/mL.
Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron
divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually
require supplemental iron to increase or maintain transferrin saturation to levels which will adequately
support erythropoiesis stimulated by PROCRIT®.
Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of
clinical trials.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not
been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations
in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV
with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.
Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses
5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT®
should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair,
delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1
fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal
wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high
as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).
Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with
PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg.
There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid
opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group.
There were no PROCRIT®-related effects on the F2 generation fetuses.
It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when PROCRIT® is administered to a nursing woman.

were determined for medications, diagnostics, office visits, and invasive procedures. Patient management costs were
based on published literature, treatment
fee schedules, and drug wholesale price
sources.
Of the pleural effusions examined, 29
(60%) were mild in severity and man-

aged medically at a cost of $750 per
episode. The remaining 19 (40%) pleural effusions were more clinically significant, and half of the patients required
invasive procedures.
The cost of inpatient invasive procedures ranged from $3807 for placement
of a shunt to $15,344 for placement of a

Strict Adherence to Indications Strongly Recommended
for ESAs
CHICAGO—Given the uncertain
effect on symptoms associated with anemia and the potential harm of using erythropoiesis-stimulating agents (ESAs)
to treat anemia, indications for treating
chemotherapy-induced anemia should
be strictly adhered to, said Fadlo R.
Khuri, MD, at the 44th annual meeting
of the American Society of Oncology.
Khuri, associate director for clinical
and translational research, Winship
Cancer Institute, Emory University,
Atlanta, Ga.; chaired a session on negotiating the conflicting demands of ESAs
and pointed to evidence that tumor
cells may use the erythropoietin system
for growth, prolonging the tumor’s sur-

vival. Randomized clinical trials of sufficient size in patients with treated head
and neck cancer and breast cancer
showed higher locoregional progression
of cancer and worse overall survival in
recipients of ESAs compared with
placebo. Although the data are incomplete, “we have three studies in the curative setting that suggest harm,” he said.
Further, randomized, placebo-controlled clinical trials in which ESAs
were studied in untreated patients with
cancer-related anemia confirmed worse
overall survival and worse disease-free
survival in those assigned to ESAs.
Further study suggests that erythropoietin receptors on cancer cells may

explain the worse prognosis observed
with ESAs in cancer patients. In radiotherapy-treated patients with head and
neck cancer, those with erythropoietinreceptor–positive disease did significantly worse when treated with epoetin
beta versus placebo, Khuri noted.
The US Food and Drug Administration (FDA) has taken note of these
studies and issued black box warnings and
safety-related changes to package inserts.
In March 2008, the FDA issued a safety
advisory, stating that ESAs were not to be
used in the context of curative therapy.
—Wayne Kuznar

Baseline Hemoglobin Level Predicts Transfusion
Risk in Patients Receiving ESAs
ANAHEIM—The hemoglobin (Hb)
level at which treatment with erythropoiesis-stimulating agents (ESAs) is initiated predicts the subsequent risk of red
blood cell (RBC) transfusion in patients
with chemotherapy-induced anemia
(CIA), according to a meta-analysis.
The findings were presented in a
poster session held during the 2008
Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners joint
annual conference.
A recent national coverage decision
(NCD) issued by the Centers for MediNovember/December 2008

care & Medicaid Services recommends
initiating ESA therapy in patients with
CIA and Hb <10 g/dL and discontinuing ESAs when Hb reaches 10 g/dL.
The impact of the NCD on transfusion
risk and other clinical outcomes in
patients with CIA has not been established.
A meta-analysis of six randomized,
double-blind, placebo-controlled studies of darbepoetin alfa in patients with
CIA was conducted by Jeffrey Crawford,
MD, and colleagues, Duke University
Medical Center, Durham, N.C. The
analysis included 1200 patients treated

with darbepoetin alfa and 912 patients
in the placebo group.
In these studies, ESA therapy was
withheld according to different criteria:
Hb >13 g/dL or >1 g/dL increase in 14
days; Hb >14 g/dL; and Hb >14 g/dL in
women and Hb >15 g/dL in men. The
end points of the meta-analysis included
the percentage of patients with at least
one RBC transfusion from week 5 to the
end of the treatment period and the incidences of death and disease progression.
In both the darbepoetin alfa and
placebo groups, the incidence of RBC
transfusion tended to be higher in

pericardial window. The cost of outpatient invasive procedures ranged from
$713 for ultrasound thoracentesis to
$4598 for placement of a pleural
catheter.
The placement of a pleural catheter
instead of repeated thoracentesis or
chest tube placement increased total
costs by about 30%. No recurrence of
pleural effusion decreased total average
costs by about 20%.
The total average cost per patient
overall was about $2000 to $2700 depending on the types of management
interventions provided. The total average cost per patient for pleural effusions
requiring invasive management procedures was about $6400 to $9000 depending on the interventions provided.
“Development of pleural effusions in
patients with imatinib-resistant or
-intolerant CML poses a significant
challenge to physicians, as they cannot
be predicted, the time of onset is variable, and management may require
invasive procedures and possible complications,” the researchers wrote. “Despite challenging adverse events, the
kinase and Abl inhibitors have been
shown to improve outcomes for patients
in various phases of CML.”
—DSM

patients with lower baseline Hb levels.
Overall and across all baseline Hb
groups, the transfusion incidence was
lower for the darbepoetin alfa group
than for the placebo group.
The hazard ratio for RBC transfusion
ranged from 0.5 in patients with baseline Hb 9 to 19 g/dL to 0.32 in patients
with baseline Hb >12 g/dL. Treatment
with darbepoetin alfa decreased the
transfusion risk compared with placebo
both overall and across all baseline Hb
subgroups.
Overall, the risk for venous thromboembolism (VTE) was higher in the
darbepoetin alfa group than in the
placebo group and was not strongly
influenced by the baseline Hb level at
which treatment with ESAs was initiated.
“This finding is in accordance with
the well-characterized VTE risk associated with ESA use in cancer patients,”
the researchers stated.
Overall and across baseline Hb
groups, the risk of death and the combined end point of death or disease progression was similar in the darbepoetin
alfa and placebo groups.
In a time-dependent covariate analysis, patients with transfusions in both
treatment groups had a higher risk for
death and for death or disease progression. In the ESA group, patients with
transfusions had increased risk for VTE.
“This meta-analysis suggests that the
NCD recommendations will increase
transfusion rates,” the researchers concluded. “Initiating ESA therapy at Hb
levels >11 to 12 g/dL resulted in the
lowest absolute risk for transfusions.”
—DSM

G REEN H ILL H EALTHCARE C OMMUNICATIONS

9

HEMATOLOGIC CANCERS

ANAHEIM—The management of
pleural effusion in patients with chronic myeloid leukemia (CML) is costly
and requires intensive resource utilization, a new study shows.
Pleural effusion is relatively common
in patients with CML and may emerge
up to 2 years after the start of therapy.
The hallmark symptoms of pleural effusion are significant cough and dyspnea.
The economic burden of pleural
effusion was determined in a literaturebased analysis of 138 patients with
CML treated with dasatinib at a single
institution. The findings were reported
by Jennifer Stephens, PharmD, and
colleagues, Pharmerit North America,
Bethesda, Md., in a poster session held
during the 2008 Hematology/Oncology Pharmacy Association/International Society of Oncology Pharmacy Practitioners joint annual
conference.
The study included an analysis of
treatment patterns and the probabilities
of events or procedures based on the
observed medical resource utilization
reported for the 48 dasatinib-treated
patients (35%) who developed pleural
effusion. The clinical management of
these 48 patients is summarized in the
Table.
Total average and item-specific costs

HEMATOLOGIC CANCERS

Pleural Effusions Costly in Patients with CML

ANDERSON INTERVIEW
Continued from cover

INTERVIEW

been here for 15 years. Before this, I was
at a downtown Boston teaching hospital for 17 years. Iâ&#x20AC;&#x2122;ve always been
involved in pharmacy administration,
particularly as it relates to operations
and financial processes.
The reason that I got involved in
oncology as a particular area of interest
really didnâ&#x20AC;&#x2122;t have to do so much with the
drugs in terms of their clinical application, but more in terms of the cost.
When I look at a budget here at Lahey
and at the inpatient and outpatient drug
costs, I find that about 70% of our total
drug costs are actually in the outpatient
clinics in the ambulatory area. Then, as I
look at the ambulatory area as a subcomponent, itâ&#x20AC;&#x2122;s mostly oncology products.
So, I developed an interest in oncology products as well as some of the
other high-cost drugs, such as the
biotech drugs. I was very interested in
the reimbursement for these products
and whether we were in fact covering
our costs or whether we should be considering this a cost center or revenue
center.
On the inpatient side, when you look at
drug expenses, you really need to look at it
from the perspective that itâ&#x20AC;&#x2122;s an expense
and revenue is pretty fixed. When you
look at the outpatient side of things, on
the other hand, revenue is not fixed.
As much as Medicare has tried to
develop a prospective system on the outpatient side, when I look across all of our
payers, and across all of the ambulatory
injectable drugs in particular, I find that
we do, in fact, make sufficient money to
cover the cost of the drugs. So, as our
budgets increase on the expense side, so
do our budgets for revenue.

How did your interests lead to
your involvement in ACCC?
I lectured a fair amount around the
country on these particular topics beginning in the late 1990s and developed an
expertise in understanding reimbursement issues, even before the Medicare
Modernization Act of 2003, and I developed some cost models that have been
used around the country. I tried to educate people on how to look at reimbursement in the outpatient sector, particularly for high-cost ambulatory drugs.
The ACCC was very interested in
the work I was doing, and they were instrumental in getting me before the
Ambulatory Payment Classification
System (APCS) panel, which makes recommendations to the Centers for Medicare & Medicaid Services (CMS).
So, my involvement in ACCC really
goes back to my interest in looking at
this whole financial perspective to
determine whether we should consider
ourselves, from the ambulatory side, a
cost center or a revenue center.

INTERVIEW

Could you tell us about ACCCâ&#x20AC;&#x2122;s
goals and the services it provides?
ACCC is a multidisciplinary organization representing physicians, nurses,
pharmacists, social workers, oncology
clinic administrators, people involved
in finance, and others who are focused
on oncology, and it has two basic missions. One is advocacy, and the other is
education.
10

physician office practices and hospitalbased practices. On the physician practice side, reimbursement is different on
the inpatient side from the outpatient
side. One of the things that we do, from
an advocacy standpoint, is to point out
those differences to CMS.
In terms of the second objective, which
is education, ACCC does a lot in terms of
education. We have two major
conferences each year, the ecoLeadership is incredibly
nomics conference in the fall
and the annual meeting in the
important to be effective as spring. At the economics conference last week, there were
clinicians, administrators, or sessions on issues like the compendia, general access to care,
and changes in reimbursement.
in other roles.

ACCC has representation and a good
reputation within the government,
both in CMS and Congress, and we
meet with government representatives
to tell the story of whatâ&#x20AC;&#x2122;s happening out
in the real world of practice.
One of the concerns that we have
always had in terms of advocacy is
access to care. ACCC represents both

Thereâ&#x20AC;&#x2122;s a lot of information for practitioners on the ACCC website [http://
www.accc-cancer.org]. We encourage
hospitals as well as private physician
practices to become members of
ACCC, which gives them access to all
of the information on both the public
and private sections of the website.
Each Monday, members receive an email newsletter called This Week at
ACCC, which provides the most recent
information available on any number of
topics that affect oncology care.

You were instrumental in
establishing OPEN within
ACCC. What services does it
provide for pharmacists?

Some of the reimbursement information that I talked about earlier and some
of the spreadsheets that I created are
posted on the website as tools to help
pharmacists do a cost analysis of particular drugs to determine if there is a margin on that drug across all of their payers. We also hold OPEN seminars
during the ACCC annual meeting
focused on topics that are particularly
relevant to oncology pharmacists.
Sometimes these sessions later get
incorporated in ACCC general sessions
because the information is of interest to
the global membership, such as a presentation a few years ago about the role
of the pharmacist in the private practice
setting.

How does OPEN differ from the
Hematology/Oncology
Pharmacy Association (HOPA)?
We certainly do not see ourselves as
competing organizations. HOPA is
made up of just pharmacists, and we
work very closely with them. The president of HOPA and I have made a commitment to work in concert with one
another and make sure that we have a
message that is very cohesive. Weâ&#x20AC;&#x2122;ve
developed a stakeholder group, and
every year when weâ&#x20AC;&#x2122;ve gone before the
APCS panel of CMS, weâ&#x20AC;&#x2122;ve gone as a
stakeholder group and come to agreement on exactly what we are going to
present. The American Society of
Health-System Pharmacists (ASHP) is

a part of that too as well as dedicated
cancer centers, the Biotechnology
Industry Organization, and even some
group purchasing organizations.

What does having for the first
time a pharmacist as president
of ACCC say about the organization and about the role of
pharmacists in cancer care?
It shows the diversity of the group,
the multidisciplinary approach it takes,
and the value that every discipline
brings to the table. One of my objectives early on in getting involved with
ACCC was to bridge not only to
HOPA, but also to bridge to ASHP. I
saw a lot of synergy between what

INTERVIEW

The executive director and I decided
to make ACCC more appealing to
pharmacists because there was not a lot
of pharmacy activity within ACCC.
One of my objectives was to try to get
more pharmacists involved because I
thought that we could bring great value
to the table and to help ACCC as an
organization. At the same time, we
wanted to show that ACCC has value
to oncology pharmacists.
So, we created OPEN with a board
that consisted of pharmacists from
around the country who either had clinical expertise in oncology or were pharmacy administrators like myself, and we
started the OPEN website, a subsection
of the ACCC website.

ACCC was doing and what ASHP was
doing, and one of my goals when I
became a member of the ACCC board
of trustees was to get more pharmacists
involved in the organization. The fact
that now we have a pharmacist as president of ACCC means that has come to
fruition. We anticipate a continuation
of this type of involvement of pharmacists in ACCC.

What are your goals for your
term as president?
One, as I just mentioned, is to
acknowledge the fact that by bringing
other organizations into the fold that
there is great synergy, and it presents a
powerful statement to the regulatory
agencies and to Congress. Another

focus this year is the theme of leadership. Leadership is incredibly important
to be effective as clinicians, administrators, or in other roles. If we want to have
a well-run oncology practice that takes
good care of patients, we need good
leadership within that.
One example of leadership is to try to
bring together ACCC and other stakeholders within the oncology community
such as HOPA, ASHP, and the
National Comprehensive Cancer Network to educate CMS on issues of reimbursement.
Another component of leadership
has to do with valuing every person
within the organization. I recently
wrote an editorial called â&#x20AC;&#x153;Leading with
Emotional Intelligenceâ&#x20AC;? (Oncology

Issues. Sept/Oct 2008. Page 5). Emotional intelligence is a topic that is very
important within any organization.
Leading with emotional intelligence
requires that the leader, first of all,
knows himself or herself and then that
the leader knows how to relate in a very
positive and constructive way with all of
the employees within that group.
One of the terms that I like a lot is
that the leaders need to be servant leaders. The concept here is that by serving
the people who work for you, you value
them, and help them be successful at
what they do. If Iâ&#x20AC;&#x2122;m successful at making
them successful, overall the whole
organization is going to grow and to
flourish.
â&#x20AC;&#x201D;Karen Rosenberg

Did you

Know?
49% of adults who have ever
taken a prescription medication report that they are only
â&#x20AC;&#x153;fairly confident,â&#x20AC;? â&#x20AC;&#x153;somewhat
confident,â&#x20AC;? or â&#x20AC;&#x153;not at all confidentâ&#x20AC;? in their knowledge about
these medications. Source:
www.harrisinteractive.com.

Leukemia Group B (CALGB) trial
79809 at the American Society of
Clinical Oncology 2008 Annual Meeting showed that zoledronic acid (ZA)
preserves bone mineral density (BMD)
in this population.
The trialâ&#x20AC;&#x2122;s primary hypothesis was
that ZA would prevent bone loss measured at the lumbar spine at 12 months
in women with chemotherapy-induced
ovarian failure. Eligible women had histologic evidence of invasive stages I-III
breast cancer, were >40 years of age,
were not pregnant, and were actively
menstruating or had their last menstrual period within the past 6 months.

trols (P <.0001). Among women
receiving ZA with or without tamoxifen, BMD percent change increases
were similar (+2.0/+2.2, respectively),
but BMD losses in the control group
were larger without tamoxifen (â&#x20AC;&#x201C;4.3/
â&#x20AC;&#x201C;9.5, respectively). Higher-grade toxicities were minimal in ZA groups.
Shapiro concluded, â&#x20AC;&#x153;Zoledronic acid
prevents bone loss in women with
chemo-induced ovarian failure, adding
minimal toxicity to adjuvant chemotherapy.â&#x20AC;? He noted further that given
every 6 months, ZA prevents bone loss in
premenopausal women receiving GnRH
agonists and would probably be effective
in chemo-induced ovarian failure as well.
Results for the secondary hypothesis,
that â&#x20AC;&#x153;earlyâ&#x20AC;? ZA would be more effective
than â&#x20AC;&#x153;lateâ&#x20AC;? ZA, remain pending.

SUPPORTIVE CARE

CHICAGOâ&#x20AC;&#x201D;Ovarian failure is induced in 50% to 70% of premenopausal
women receiving chemotherapy. Bone
loss in the lumbar spine attributed to
estrogen deficiency in these women is
similar to that seen with gonadotropinreleasing hormone (GnRH) agonists
and is roughly threefold higher than
that seen with aromatase inhibitor therapy, said Charles L. Shapiro, MD, Ohio
State University, Columbus.
â&#x20AC;&#x153;This rapid bone loss should be prevented, because it may increase the risks
of osteoporosis in some breast cancer
survivors,â&#x20AC;? Shapiro said. His report of
first results from the Cancer and

They received adjuvant chemotherapy
with/without tamoxifen, 1000 mg calcium, and 400 IU of vitamin D.
Intravenous ZA (4 mg) was given every
3 months for 2 years starting immediately in one group (â&#x20AC;&#x153;earlyâ&#x20AC;?) and after 12
months in the other (â&#x20AC;&#x153;lateâ&#x20AC;?). Controls
did not receive ZA.
Among 439 women randomized,
ovarian failure, defined as amenorrhea
>3 months, occurred in 166 women.
Mean age was 47 years, and mean lumbar spine BMD was 1.14 g/cm2.
Seventy-five percent of women in the
ZA group (n = 81) and 62% of women
in the control group (n = 85) planned to
take tamoxifen.
Mean percent change in BMD was
+2.2 in the ZA group and â&#x20AC;&#x201C;6.6 in con-

â&#x20AC;&#x201D;Walter Alexander

Synchronizing ESA and
Chemotherapy Treatments
Potential Opportunity for
Convenience and
Cost-savings
KANSAS CITY, MOâ&#x20AC;&#x201D;More than
30% of treatments with erythropoiesisstimulating agents (ESAs) were given
during separate visits from chemotherapy treatments, according to a retrospective study of a large database of
more than 185,000 patients with cancer
reported at the 2008 Educational
Conference of the Academy of Managed Care Pharmacy (AMCP).
The authors suggest that synchronization of ESA therapy and chemotherapy
is an opportunity for cost-savings and
greater patient convenience compared
with separate visits to the clinic for each
form of therapy. Of available ESAs, epoetin alfa was associated with significantly more nonchemotherapy clinic visits
than darbepoetin alfa, presumably because of a more rigid dosing schedule for
epoetin alfa. Recent studies have shown
that darbepoetin alfa can be given every
3 weeks, whereas epoetin alfa requires
more frequent office visits.
â&#x20AC;&#x153;Synchronization of therapy should
reduce travel to and from the clinic and
reduce patientsâ&#x20AC;&#x2122; costs and time allotted
for additional visits,â&#x20AC;? said lead author
Beth L. Nordstrom of United BioSource
Corporation in Lexington, Mass.
Nordstrom noted that a prospective
study is needed to confirm the safety
and cost-savings of synchronization of
these two forms of therapy.
The study utilized a database provided
by Varian Medical Oncology comprising
electronic medical records from outpatient oncology clinics in the United
States. The study population included
8044 adult patients with breast, lung,
colorectal cancer, or lymphoma treated
with systemic antineoplastics, including
at least one conventional myelosuppressive agent, on a regular schedule. All
patients received at least two ESA treatments during conventional chemotherapy (4484 on darbepoetin alfa and 3560
on epoetin alfa) between January 1,
2002, and June 30, 2007.
Compared with patients who received
Continued on page 15

number of services that particularly
benefited managed care organizations
and their members.
Driven by their success in other disease areas, specialty pharmacies then
expanded to oncology. Under the bestcase scenario, oncology specialty pharmacies may be contributing to patient
care and affordability. Under less ideal
circumstances, however, there may be
concerns.

PHARMACY PRACTICE

Why the need for oncology
specialty pharmacies?
Approximately 9 million Americans
are living with cancer, and the need for
payers to control the cost of their treatment is the prime rationale. Payers have
issues with the “buy and bill” model,
that is, the system in which a large share
of an oncologist’s income is derived
from buying drugs at wholesale and selling them at retail. The perception is
one of inconsistency and variation in
drug use, excessive off-label drug use,
and wasteful management strategies by
physicians, says Dawn G. Holcombe,
FACMPE, ACHE, MBA, president of
DGH Consulting, South Windsor,
Conn., and executive director of the
Oncology Network of Connecticut.
Elan Rubinstein, PharmD, MPH,
principal of EB Rubinstein Associates, a
healthcare consulting firm in Oak Park,
Calif., says, “It comes down to dollars,
and payers are driving all this. It costs
payers much less to have the drug go
through pharmacy [benefits program]
than for the doctor to give it.”
The cost-control mandate also happens to converge with the emergence of
oral therapies, which has opened the
door for specialty pharmacies, since
direct-to-patient shipping is a key part
of the business model. Some 30% or
more of new pipeline products are oral
formulations, and some states actually
forbid oncologists from dispensing oral
agents in their offices.
Lee Newcomer, MD, senior vice president of oncology for UnitedHealthcare, adds that oral oncology drugs can
be seen as a “second chance to get some
things right,” such as “correcting the
strategic errors from buy and bill in the
physician’s office.”
Advocates of specialty pharmacy say
that this system can best adapt to the
handling and storage requirements of
oncolytics and to the field’s complex
Medicare reimbursement issues. The
provision of value-added services is also a
selling point to payers, including educational resources, patient safety and compliance tracking, and reimbursement
assistance. When carried out successfully,
these features provide a strong rationale
for oncology specialty pharmacy, says
Mark Neville, vice president of sales and
marketing for Diplomat Specialty
Pharmacy, the largest independently
owned pharmacy in the country.
“Oral oncolytics is our core model
because of limitations in distribution,
the cost, the need for assistance with
patient copays, and the difficulties in
keeping patients on the drug to achieve
proper outcomes,” he says. Oncology
specialty pharmacy, he notes, helps to
combat the “perfect storm of cost and
14

complexity” in the treatment of cancer.
In the current environment, cost
control is clearly an area where oncology specialty pharmacy can have an
impact, and not just in the form of discounts and rebates for payers, according
to Neville. “Oncology is probably in a
class by itself with regard to the magnitude of the cost of treatment.”
“We talk to patients daily who are
deciding between filling their prescription and refinancing their house or selling their car. The Medicare Part D
‘doughnut hole’ is $4050. Once patients
get past this, they are still responsible
for 5% of the total prescription cost. We
arrange copay assistance for them, and
if funds are left over, we apply these to
future pharmacy costs,” he said. “We do
all this for patients behind the scenes.
Many patients have no idea that
resources like this exist.”

Value-added services
Other value-added services also set
oncology specialty pharmacies apart.
“The 24-hour availability of the pharmacist or nurse helps ensure treatment
safety, reduces the expense of poorly
managed side effects, and helps to control complications associated with drug
interactions,” says Bob Crutchfield, vice
president and general manager of US
Oncology’s pharmaceutical services
division.
Pharmacy staff also provides regular
reports to the patients’ physicians.
“Outside retailers often lack the oncology expertise necessary to provide counseling, follow-up, or compliance support, so much of that responsibility falls
to the physicians who are already timeconstrained. We help extend the care
while keeping physicians involved.”
Neville agrees. Speaking of Diplomat’s value-added service, he describes
the management of patients receiving
erlotinib, which causes rash. “We provide education, cream for the potential
rash, and outbound nursing calls a couple of days after the first drug shipment,
midway through the first treatment
cycle, and at the time of the first refill
[by phone], to proactively manage the
rash and assure there is no gap in treatment,” he says.
Not so fast
Some oncology healthcare consultants are not completely sold, however.
“Managed care still doesn’t quite know
how to handle oncology and its rising
costs, and they are looking for answers.
But there are a lot of opinions and disconnects among parties,” says Holcombe. She maintains that oncology is
different from other fields in which specialty pharmacy has demonstrated benefits and therefore may not be compatible with the specialty pharmacy model.
“Specialty pharmacy has done a good
job in other settings where physicians
are not as involved in symptom management,” she said, alluding to one of
the greatest areas of concern—safety
and toxicity. Other concerns include
monitoring for compliance, issues of liability, waste of drug, and, the potential
loss of revenue derived by in-office infusions. While specialty oncology pharmacy currently distributes only oral
agents and self-injectables, discussions
about specialty pharmacy–operated

G REEN H ILL H EALTHCARE C OMMUNICATIONS

infusion centers have begun, she says.
While oral drugs may seem to be safer
and also perhaps easier for patients to
take, they are still toxic, and compliance with oral therapy has not been
demonstrated, she points out. Furthermore, since oral agents are often delivered as part of a regimen that includes
intravenous agents as well, separating
the two treatments seems irrational to
some. Chemotherapy treatments are
often delayed or dose-reduced because
of conditions that are identified just
before treatment, and under these circumstances, there are concerns about
wasting drug under the direct shipment
model, Holcombe notes.
Under the specialty pharmacy model,
drug delivery is no longer a “triangle”
formed by oncologists, patients, and
payers. Oncologists, therefore, are skeptical and hesitant. Many view specialty
oncology pharmacists as “middlemen”
to whom they are relinquishing control
of patient care, according to Holcombe.
“Many doctors are fighting this, not
just because they want to keep the revenue in their own hands but because
separating the drugs from the treatment
seems counter to the natural delivery of
patient care,” she comments.

Not all specialty pharmacies
created equal
Oncologists have reason to be wary,
acknowledges Neville. “There is truly a
spectrum of service. On one end, there
is a ‘lick, stick, and ship’ model that is
payer-driven and that lacks the built-in
financial margin with which to provide
value-added services to the patient. At
the other end is a very ‘high-touch’
model that takes all-comers, finds copay
assistance (beyond providing a website
address), provides patient education
and support, offers special compliance
packaging, and so forth,” he explains.
Diplomat falls into the latter category,
he adds. “We have a full team that is very
drug- and disease-specific, who do everything they can on behalf of the patient,
the oncologist, the nurse, and the case
manager at no additional charge.”
Rubinstein agrees that value-added
services are not a given with all specialty pharmacies. “It depends on the margin for the drug. A recent survey found
that payers are compensating for the
cost of oncology drugs by transitioning
to an average sales price (ASP)-based
payment system with different markups.
The thinner the markup, the less
money there is to play with,” he says.1
“Services are nice, but pharmacies get
paid for filling prescriptions. As margins
come down, it gets harder to justify
extra services,” he notes. “The concern
is that with payers going to the [ASP]
model, will there be margin left for specialty pharmacies to do these things, or
will they turn into fancy mail-order
companies that frankly don’t provide
much?”
Addressing the issues
Whether these issues can be satisfactorily resolved is unclear, as no clear
model for oncology specialty pharmacy
has been established, says Holcombe.
“When you drill down and look at
where specialty pharmacy is being used
in oncology, it is predominantly in areas
where Medicaid has required it and the

physician cannot afford to provide drugs
any other way,” she observes.
And don’t look for issues to be settled
on the policy level, she adds. For
instance, the competitive acquisition
program—“the federal experiment in
using specialty pharmacy to provide
oncology drugs”—had only one bidder,
BioScrip, which has not renewed its
2009 contract. “The smarter thing,” she
says, “would be for all parties to sit down
together and look at the realities of
patient care.”
—Caroline Helwick

It All Started
with Biologics
In 1994, Biologics, headquartered in Cary, N.C., became the
country’s first oncology specialty
pharmacy and remains the only
one dedicated solely to oncology.
President Robin Smith, who
launched the company, told The
Oncology Pharmacist, “We concentrate on what we know best, and
that’s cancer care. We have the
flexibility to address all 300 types
of cancer since our model is not
‘one size fits all.’ Our laser-like
focus on cancer gives us the
opportunity to build out various
business units within the cancer
umbrella,” Smith said.
Besides serving the prescription needs of 18,000 cancer
patients, Biologics is an oncology
management company and, for
the past 12 years, has run a clinical trials unit that not only distributes drugs but is involved in
trial design, budgeting, patient
enrollment, database development, placebo management, protocol review, and so forth. Having
insight into drugs in the pipeline
gives her company a heads-up
before new drugs transition into
clinical use, Smith added.
Biologics also has a proprietary
information technology platform,
ClinImpact, which helps define
and customize clinical metrics
data for payer clients. The data
include, for example, outcomes
and pharmacogenomics information that clients use to “track and
trend” such things as laboratory
values and comorbidities based
on demographics, disease state
and stage, sex, and so forth.
This service fills a need for
informatics within the industry,
Smith maintained. “Return on
investment will be huge going
forward. We are talking about
expensive therapies, and payers
want to see some return on their
dollars,” she said.

November/December 2008

Continued from page 13

epoetin alfa, those who received darbepoetin alfa had a lower minimum hemoglobin level during the chemotherapy
episode of care; were more often on
every-2-weeks chemotherapy regimens
and less often on weekly chemotherapy
regimens; and were more often on every2-weeks or every-3-weeks ESA schedules
and less often on weekly ESA schedules.
Because darbepoetin’s every-3-weeks
schedule was approved in 2006, the
authors studied chemotherapy and ESA
schedules during two different periods:
2002-2005 and 2006-2007. Patients on
an every-3-weeks chemotherapy schedule received darbepoetin alfa every 2
weeks more often in 2002-2005, but the
every-3-weeks schedule for darbepoetin
alfa was used more frequently in 20062007. Epoetin alfa was dosed weekly in
all patients more often during both time
periods.
More frequent synchronization of
chemotherapy and ESA therapy was
associated with darbepoetin alfa compared with epoetin alfa, more frequent
chemotherapy schedules, hospitalbased clinics compared with community clinics, Northeast and Midwest
regions of the United States compared
with South and West regions, lower
minimum hemoglobin levels during the
regimen, and colorectal and breast cancer compared with lung cancer and
lymphoma.

About 20% to 25% of all breast cancers are HER2 positive. The survival benefit of trastuzumab, directed against the
HER2 protein, is confined to HER2-positive patients. Thus, HER2 testing should
be standard before initiating trastuzumab.
The study was based on 405 members
who filed at least one medical claim for
trastuzumab from November 2006
through October 2007. Claims for
HER2 testing were identified for 106
(26.2%) members. Medical records
were requested for 299 members
(72.3%) with no medical claims billed
for a HER2-related laboratory test. The
type of HER2 test, date of the test, and
test results were recorded. HER2 testing
was performed or assumed to be performed in 375 (92.3%) of 405 members.

Review of medical records showed that
97.8% of patients taking trastuzumab
were HER2 positive.
Using medical claims history as the
sole method for determining drug utilization may be insufficient, Chang
commented. In this study, medical
claims accounted for only 26% of members receiving HER2 testing. Medical
records of the population without
claims data showed that HER2 testing
was actually performed in 92% of those
receiving trastuzumab (more than the
estimated 26% reflected in claims data).
She noted that the inaccuracy of medical claims may be due to bundling of
claims with no specific codes in the hospital setting, testing done outside the
date span of the study, and providers’

inconsistent use of Current Procedural
Terminology codes for HER2 testing.
Chang said that medical records
review is the best way to confirm HER2
testing. A cost analysis showed that prior
authorization review for HER2 testing
for members receiving trastuzumab
would have yielded a low return on
investment, ranging from 1.7% (best
case) to 14.2% (worst case).
“This drug utilization review reveals
that oncologists are following the standard of care, and suggests that implementing a prior authorization on
trastuzumab is unnecessary and places a
burden on the physician, patient, and
health plan,” Chang stated.
—AG

ON DEMAND
FREE CONTINUING EDUCATION CREDITS
www.COEXM.com strives to provide the most up-to-date clinical information that
will improve cancer care and outcomes for patients through specialty products,
across multimedia platforms, reaching multiple stakeholders and customers.

—Alice Goodman

KANSAS CITY, MO—The majority
of oncologists under the Regence Group
(an affiliation of BlueCross BlueShield
health plans in the Pacific Northwest)
are following American Society of
Clinical Oncology and National Comprehensive Cancer Network recommendations for human epidermal growth factor receptor 2 (HER2) testing for patients
with invasive breast cancer before initiating trastuzumab (Herceptin), according
to a drug utilization review for trastuzumab from its pharmacy benefit management, RegenceRx. More than 90% of
health plan members who were taking
trastuzumab had confirmed HER2 testing, suggesting that prior authorization is
not necessary for patients prescribed
trastuzumab.
“The study suggests that prior authorization review of all trastuzumab claims
to review for HER2 testing may yield a
low return on investment. More efficient use of health plan resources may
be directed towards educational outreach to prescribers to encourage HER2
testing of breast cancer patients before
starting trastuzumab,” according to
Crystal Chang, who conducted the
review for RegenceRx. Chang, who is a
fourth-year Doctor of Pharmacy degree
candidate at University of Southern
California School of Pharmacy, presented her poster on HER2 testing at the
2008 Educational Conference of the
Academy of Managed Care Pharmacy.
November/December 2008

Current activities at www.COEXM.com include:
• Considerations in Multiple Myeloma: Health Economics • Perspectives on the Treatment
of Colorectal Cancer • Perspectives on the Treatment of CTCL and PTCL • Developments in
the Treatment of Metastatic Breast Cancer • Perspectives on the Treatment of Lung Cancer
FREE CE newsletters
at www.COEXM.com

A vast array of career opportunities
for pharmacists is available, making it a
worthy and marketable healthcare profession to pursue. This array of opportunities is accompanied by the need for
plenty of background research to find
the career path that fits a desired
lifestyle. While changes in the direction
of one’s career can occur at any time,
one should become aware of all opportunities available as a licensed pharmacist. Strategic career planning should
begin as early as possible and is imperative to allow for the development of
knowledge and skills for advancement
and to avoid career pitfalls.
Many pharmacy students and residents are not aware of the numerous
public health opportunities for pharmacists. A variety of public health opportunities for pharmacists are available at
the US Food and Drug Administration
(FDA). The FDA is responsible for protecting the public health by assuring the
safety, efficacy, and security of human
and veterinary drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation. The FDA helps the public obtain
accurate, science-based information needed to use medication and foods to
improve and manage their health. The
FDA has a complex organizational
structure composed of offices and centers. The centers are composed of
offices, which are further structured into
divisions. This complexity attests to the
FDA’s substantial growth since its 1862
inception as the Bureau of Chemistry, in
the US Department of Agriculture.
Additional information about the
FDA’s history can be found at
http://www.fda.gov/oc/history/history
offda/default.htm. Links to charts displaying the FDA organizational structure are located at http://www.fda.gov/
opacom/7org.html.
The FDA employs more than 300
pharmacists in more than 150 cities
nationwide.
Pharmacists are employed in various
positions within the FDA and have
gained employment at various points in
their careers. However, the majority of
pharmacists hired have had at least 2
years of experience in clinical or community practice. Pharmacists are employed in the Office of the Commissioner, the Office of Regulatory Affairs,
and within the six centers of the FDA.
Depending on experience and education, a pharmacist may work as a
reviewer in clinical pharmacology, pharmacokinetics, pharmacology/toxicology, regulatory, or radiopharmacology.
Also, pharmacists may work as regulatory health project managers, also known
as consumer safety officers, in one of the
offices under the Center for Drug
Evaluation and Research (CDER) Office of New Drugs. The consumer safety
officer position is an excellent starting
16

Table. Examples of Pharmacist Positions and Duties at the FDA, Center for Drug Evaluation and Research
Location

Title

General summary of duties

Office of New Drugs

Regulatory project manager/
consumer safety officer

Office of New Drugs

Clinical analyst reviewer

OSE/Division of
Pharmacovigilance or Division of
Medication Error Prevention and
Analysis

Safety evaluator

OSE/Division of Epidemiology

Drug utilization data analyst

Provide regulatory oversight and advice to multidisciplinary teams
and pharmaceutical industry during the NDA approval process,
coordinate the review of drug applications, serve as liaison between
industry and FDA, facilitate internal FDA meetings and external
meetings with industry
Conduct reviews of clinical study protocols, review and evaluate
reports and data from clinical trials submitted in INDs, NDAs, and
BLAs to verify safety and efficacy of drug products. Provide advice
on design of clinical studies, recommend approval of applications,
and evaluate product labeling
Review and evaluate spontaneous adverse event reports submitted
by manufacturers, healthcare professionals, and consumers; review
medication error reports; participate in risk management program
development and monitor the impact of the program; participate in
preapproval safety conferences between the FDA and drug sponsors and in FDA advisory committee meetings
Analyze national drug utilization data obtained from specialized
database searches as related to public health and safety concerns,
collaborate with other divisions in OSE to evaluate the magnitude of
adverse drug events and drug risk
Review and evaluate promotional materials for prescription drug
products to ensure compliance with the federal Food, Drug, and
Cosmetic Act and various regulations pertaining to the advertising
of prescription drug products
Advise and assist the director, Division of Training and Development,
the Committee for Advanced Scientific Education, appropriate
CDER coordinating committees, and related industry and
academic organizations, scientific experts, and scientific staff
throughout CDER, as well as FDA officials on the program planning,
evaluation, and conduct of CDER’s science-based educational activities. Prepare documents, including program management data, and
correspondence related to the accreditation of CDER’s continuing
medical education and continuing pharmaceutical education programs. Assure compliance with criteria for administration, conduct,
and evaluation of these programs
Verify that sponsor has submitted labeling in compliance with Code
of Federal Regulations, serve as liaison between industry and FDA
on issues related to label requirements, critically assess proposed
labeling of approved abbreviated NDAs and supplements in terms
of appearance, content, regulatory compliance, and safety
Conduct reviews of clinical pharmacology and biopharmaceuticals
data and use technical tools (eg, modeling and simulation) in support of CDER’s IND, NDA, and BLA review program to determine relevant clinical issues and exposure–response, drug–drug interactions, pharmacokinetics, effect of clinical pharmacology on dosing
and administration, dosing regimen adjustments, and issues that
impact labeling
Conduct inspections of pharmaceutical manufacturing facilities to
evaluate current good manufacturing practices (cGMPs) compliance, review inspection reports from other FDA investigators to
determine need for regulatory or administrative action, initiate regulatory or administrative action ensuring corrected deficiencies,
answer (cGMP) inquiries, provide oversight and advice to FDA staff
and pharmaceutical industry on cGMPs and conducting pharmaceutical inspections, draft and review cGMP guidance documents,
and train FDA field investigators

Office of Medical Policy/Division of Regulatory review officer
Drug Marketing, Advertising, and
Communication
Office of Training and
Communications/Division of
Training and Development

point for a pharmacist’s career in the
FDA. Pharmacists are commonly hired
for these positions not only for their scientific knowledge, but also for their
attention to detail, communication,
and organizational skills. In addition,
pharmacists may work as safety evaluators, drug utilization analysts, labeling
reviewers, field inspectors, compliance
officers, or on expert advisory committees and review panels. Additional
information on opportunities for pharmacists at other Department of Health
and Human Services (DHHS) agencies
can be found at http://www.hhs.gov/
pharmacy/agencies.html#FDA.
The Table provides a list of examples
of various positions and duties performed by pharmacists for the FDA in
the CDER. This list is not inclusive of
all potential opportunities for pharmacists at the FDA.
Pharmacy students interested in a
career at the FDA should participate in
the FDA Pharmacy Student Experiential Program. This program provides
an opportunity for pharmacy students in
their last year of pharmacy school to
learn about FDA laws, regulations, and
guidance governing drugs, biologics,
and devices for human use during a 4- to
6- week rotation. Participating students

WORK SURFACE SAMPLING
Continued from cover

joint annual conference, raise important
questions about pharmacy workplace
safety and the effectiveness of routine
pharmacy cleaning and decontamination
procedures.
Strategies for the protection of pharmacy employees against the carcinogenic, mutagenic, and reprotoxic effects
of antineoplastic drugs have been
implemented and improved during the
last decades, but contamination of personnel and the workplace with these
compounds still occurs. Regular monitoring of antineoplastic drug contamination in pharmacies may be a useful
means of determining the effectiveness
of decontamination strategies and provide input for the development of

may attend FDA advisory committee
meetings and congressional hearings.
Additionally, the program provides academic credit hours required for the
Doctor of Pharmacy degree. More information about this program can be located at http://www.fda.gov/Cder/Offices/
DDI/pharmstudent.htm.

are assisted financially during their
final year of pharmacy school in return
for an agreement to work for the
USPHS after graduation. The student
is appointed as an active-duty USPHS
officer during the senior year and
receives monthly pay and allowances as
an Ensign (0-1) grade officer. The stu-

Pharmacy students interested in a career at
the FDA should participate in the FDA
Pharmacy Student Experiential Program.
Pharmacy students should consider
the United States Public Health
Service (USPHS) extern programs as
an opportunity for experiential training
at various DHHS agencies, including
the FDA. This program offers paid
employment and other excellent benefits. There are two opportunities to participate while still in pharmacy school.
The Junior Commission Officer Student Training and Extern Program
(COSTEP) is available to students who
are enrolled in a professional accredited
school of pharmacy. Junior COSTEP
allows students to serve in assignments
at any time during the year for 31 to
120 days. In Senior COSTEP, students

dent agrees to work for the program
that provided the financial support for
twice the time supported following
graduation. For more information
about COSTEP, contact the Office of
Commissioned Corps Operations at
800-279-1605. Ask to speak to the
Commissioned Officer Student Training and Extern Program Coordinator.
Pharmacy residents or graduating
pharmacy students considering a career
in public health should apply for a commission in the USPHS. The USPHS is
the principal component of the DHHS.
USPHS Commissioned Corps pharmacists are employed in various DHHS
agencies, including the FDA. A career

thresholds and guidelines for the safe
handling of antineoplastic and other
hazardous drugs.
As part of an effort to achieve compliance with workplace safety regulations recently implemented in Germany, researchers from the Institute of
Energy and Environmental Technology,
Duisburg, identified the antineoplastic
drugs most commonly handled by pharmacies in that country. For 17 of the 25
most frequently handled compounds,
sampling and analytical methods for
routine contamination monitoring have
been established and validated.
The identification of suitable sampling strategies for these drugs included
the selection of media to be monitored
(eg, ambient air, work surfaces, textiles),
sampling techniques and locations, and
the timing and frequency of sampling.
For the remaining eight drugs (Table), a
program of workplace surface wipe sampling and testing (Monitoring Effect
Study of Wipe Sampling in Pharmacies
[MEWIP]) was developed and implemented in 130 pharmacies (78 hospital
and 52 public pharmacies) in Germany in
2006. The goals of the MEWIP program
were to establish the feasibility of wipe
sample monitoring, baseline levels of work
surface contamination, and the long-term
effects of routine ambient monitoring on
pharmacy contamination levels.
The participating pharmacies were
divided into two groups: the monitoring
group (55 pharmacies) performed work
surface wipe sampling every 3 months
and received the results of contamination testing (and thus had the opportunity to take targeted actions to decrease
contamination levels), and the control
group (75 pharmacies) performed sam-

pling only at baseline and the conclusion of the 15-month program.
The designated pharmacy work surface sampling locations were the floor in
front of the most intensively used safety
cabinet, the most intensively used countertop, and the refrigerator door and
handle. Wipe samples were obtained
using standardized materials and procedures and were taken from 900 cm2
areas by pharmacy personnel at the end
of the work day but before cleaning of
the respective surfaces.
A total of 1272 wipe samples were
obtained during the course of the program, resulting in 10,176 measured values. Overall, 61% of the sampled surfaces revealed contamination with at
least one of the eight investigated drugs,
reported T.K. Kiffmeyer and colleagues.
The highest percentage of contaminated wipe samples (73%) came from
the pharmacy floors. Contamination
with at least one drug was detected in
61% of the samples from countertops
and 49% of the samples from refrigerator doors.
Cyclophosphamide was the drug most
frequently detected (37% of the surfaces), followed by gemcitabine (32%),
5-fluorouracil (31%), and ifosfamide
(21%). The four remaining drugs were
detected on a maximum of only 5% of
the work surfaces sampled.
Little correlation was observed
between work surface contamination
levels and the responses to questionnaires regarding pharmacy work practices. In particular, the levels of work
surface contamination were not influenced by the amounts of drug processed
or the frequency of cleaning of the
respective work surface.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

in the USPHS Commissioned Corps
provides both career and quality-of-life
benefits. While protecting, promoting,
and advancing the public health of the
nation, Commissioned Corps pharmacists can enjoy benefits including an
accession bonus, 30 days of paid annual
leave, medical and dental benefits,
access to military bases around the
world, use of the GI bill to advance education, and access to the Veterans
Administration loan program. Additional information on the USPHS
Commissioned Corps can be found at
http://www.usphs.gov/ or contact the
Office of Commissioned Corps Operations at 800-279-1605.
Licensed pharmacists seeking employment at the FDA, whether as a
Commissioned Corps pharmacist or a
civil servant pharmacist, should apply
online at http://jobsearch.usajobs.gov.
USAJOBS is the official job site of the
United States Federal Government,
and pharmacists should apply to the
pharmacist recruitment bulletin, which
includes pharmacists’ positions for various FDA offices and centers.

In contrast, a significant correlation
was observed between the level of contamination and the procedures for the
disinfection of drug vials before they
are put into the safety cabinets.
Spraying of disinfectant (eg, isopropanol) onto the drug vials resulted
in higher levels of cyclophosphamide
contamination on all work surfaces
sampled than wiping the vials or using
no disinfection.
A tendency towards higher levels of
contamination was observed in pharmacies where the air from the safety cabinet was recirculated into the work
room. This configuration was observed
in only 21% of the pharmacies studied.
No significant decreases in the proportion of contaminated work surfaces
were observed in either group during
the course of the 15-month program.
The overall contamination load decreased in the monitoring group during
the study.
Most of the MEWIP participants
expressed satisfaction with the wipe
sampling and monitoring procedures,
and two thirds of the pharmacies reported planning consequences based on the
monitoring results. Most of the participants agreed to accept or consider ongoing contamination monitoring.
The researchers said that safe work
surface contamination thresholds have
not been established for most antineoplastic drugs. They noted that absolute
work surface contamination levels may
be less important than levels relative to
those in other facilities and changes in
levels over time or in response to revised
cleaning or decontamination procedures.
—DSM
November/December 2008

You prepare anthracyclines, but are you prepared
for an anthracycline extravasation?
NEW LOWER PRICE OPTION Now Available

Totect® (dexrazoxane for injection)
is indicated for the treatment of
extravasation resulting from
IV anthracycline chemotherapy.

First and only FDA approved treatment of anthracycline extravasation, supplied as a
convenient and accessible complete three day emergency treatment kit.
Demonstrates 98% overall efficacy in preventing the need for surgical
debridement based on two biopsy-confirmed clinical trials.1
May minimize the potentially unavoidable consequences of anthracycline extravasation:
o Healthcare costs related to surgical debridement and plastic surgery
o Postponement of a patient’s chemotherapy treatments
o Long-term care and follow-up
May include a 6-year replacement kit policy that virtually eliminates the cost and concern
of drug expiration. The replacement kit policy is included at a higher price option.
See accompanying brief summary for further information

For more information, call 866-478-8274 or visit our website at www.totect.com
To order Totect®, contact one of our authorized distributors:

Visit us at the ASHP 43rd Midyear
Meeting and Exhibition Booth #1415
1

Totect® – Brief prescribing information Please
refer to the package insert for full prescribing information.
Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent.
Indication: Treatment of extravasation resulting from
IV anthracycline chemotherapy. Dosage and administration: Administration of Totect should begin as soon
as possible and within 6 hours following the anthracycline
extravasation. Totect should be given as an intravenous
(IV) infusion once daily for 3 consecutive days. The dose
of Totect is based on the patient’s body surface area: day
one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500
mg/m2. For patients with a body surface area of > 2 m2,
a dose of 2000 mg should be given on days 1 and 2, and
a dose of 1000 mg should be given on day 3. The Totect
dose should be reduced 50% for patients with creatinine
clearance values of <40 mL/minute. Cooling procedures
such as ice packs should be removed from the affected
area at least 15 minutes prior to Totect administration.
Totect (dexrazoxane for injection) must be reconstituted
with diluent, supplied in the carton. The patient’s Totect
dose is diluted in 0.9% 1000 mL NaCl prior to administration. Contraindications: None known. Warnings:
Pregnancy Category D. Dexrazoxane was toxic to pregnant
rats at doses of 2 mg/kg (1/80 the human dose on a mg/
m2 basis) and embryotoxic and teratogenic at 8 mg/kg
when given daily during the period of organogenesis.
Teratogenic effects in the rat included imperforate anus,
microphthalmia, and anophthalmia. In offspring allowed
to develop to maturity, fertility was impaired in the male
and female rats treated in utero during organogenesis at 8
mg/kg. In rabbits, doses of 5 mg/kg daily during the period of organogenesis caused maternal toxicity and doses
of 20 mg/kg were embryotoxic and teratogenic. Terato-

genic effects in the rabbit included several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous,
eye and cardiac hemorrhagic areas, as well as agenesis of
the gallbladder and of the intermediate lobe of the lung.
There is no adequate information about the use of Totect
in pregnant women. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to
the fetus. Precautions: Totect is a cytotoxic drug. When
administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur.
Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Reversible elevations of
liver enzymes may occur. Blood counts and liver enzymes
should be monitored. Greater exposure to dexrazoxane
may occur in patients with compromised renal function.
The Totect dose should be reduced by 50% in patients
with creatinine clearance values <40 mL/min. Dimethyl
sulfoxide (DMSO) should not be used in patients who
are receiving dexrazoxane to treat anthracycline-induced
extravasation. Women who have the potential to become
pregnant should be advised that Totect might cause fetal
harm. There are no known drug interactions. No carcinogenicity studies have been done with Totect in animals.
The carcinogenic potential of dexrazoxane has not been
investigated. Long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer
ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not
mutagenic to bacteria in vitro (Ames assay), but caused
significant chromosomal aberrations in mammalian cells
in vitro. It also increased the formation of micronucleated
polychromatic erythrocytes in mice. Dexrazoxane is mu-

Rx only
Totect® is a registered trademark of
TopoTarget A/S
US Patent No. 6,727,253B2

Manufactured by:
Ben Venue Laboratories, Inc.
Bedford, OH 44146

NDC 38423-110-01

Hameln Pharmaceuticals GmbH
31789 Hameln
Germany

tagenic and clastogenic. The possible adverse effects of
Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied.
Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in
rats (about 1/5 the human dose on a mg/m2 basis) and as
low as 20 mg/kg weekly for 13 weeks in dogs. The effect
of dexrazoxane on labor and delivery in humans has not
been studied. It is not known whether dexrazoxane or its
metabolites are excreted in human milk. Because many
drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants
from dexrazoxane, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
The safety and effectiveness of Totect in pediatric patients
have not been established. No differences in safety or efficacy were observed between older and younger patients,
and other reported clinical experience has not identified
differences in responses between the elderly and younger
patients, but greater sensitivity of some older patients has
been observed. This drug is known to be substantially
excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function. Adverse reactions: Adverse reactions of nausea/
vomiting, diarrhea, stomatitis, bone marrow suppression
(neutropenia, thrombocytopenia), altered liver function
(increased AST/ALT), and infusion site burning have been
observed. These adverse reactions have been reversible.

HOW TO RECEIVE CREDIT
To receive continuing education credit, learners must:
• Read the article in its entirety.
• Take the CE self-assessment test and complete the evaluation test:
1. Log on to www.theoncologypharmacist.com.
2. Click on UNMC logo on homepage.
3. Register to participate.
4. Enter program number #CIK9976.
• The learner must answer at least 70% of the questions on the post-test correctly.
• The estimated time to complete this activity is 1 hour. Your continuing education
certificate can be printed by following the directions online after successful completion of the post-test and evaluation.
TARGET AUDIENCE
Registered pharmacists and other interested healthcare professionals, especially
those caring for cancer patients.

O

ur recently published reanalysis of the Prostate Cancer
Prevention Trial (PCPT) appears to settle the issue of finasteride’s role in prostate cancer prevention. My colleagues
and I reported that the 5-alpha-reductase inhibitor reduced risk of
prostate cancer detection by 30% in healthy men >55 years of age
without the increased rate of detecting high-grade tumors (Gleason
grade >7) seen in the initial study.1,2 An accompanying editorial
supports our findings, stating that “finasteride is a safe and effective
prevention option that should be offered to men at risk for prostate
cancer.”3
Increased detection of high-grade malignancies in the initial study
appeared to primarily reflect improved screening properties of
prostate-specific antigen (PSA) testing and digital rectal examination
(DRE) as well as an increased sensitivity for detecting such tumors on
biopsy in men receiving finasteride rather than any effect of finasteride on the biology of cancer progression.1 The increased biopsy sensitivity most likely resulted from the prostate gland shrinkage associated with finasteride, in line with its approved use in benign prostatic
hypertrophy.1,4

FACULTY/PLANNER DISCLOSURES
It is the policy of the University of Nebraska Medical
Center, Center for Continuing Education that all planners
and faculty participating in continuing education activities
provided by the University of Nebraska Medical Center,
Center for Continuing Education are to disclose to the
audience any real or apparent conflicts of interest with
providers of commercial products and/or devices relating
to the topics of this educational activity and also disclose
discussion of labeled/unapproved uses of drugs or devices
discussed in their presentation. The planners and faculty
have been advised that this activity must be free from
commercial bias and based upon all the available scientifically rigorous data from research that conforms to
accepted standards of experimental design, data collection, and analysis.
The following authors, reviewers, and planning committee

November/December 2008

COST
This program is complimentary for all learners.
DISCLAIMERS
The opinions or views expressed in this continuing education activity are those of
the faculty and do not necessarily reflect the opinions or recommendations of the
University of Nebraska Medical Center (UNMC), Center for Continuing Education.
While the University of Nebraska Medical Center, Center for Continuing Education is
an ACPE-accredited organization, this does not imply endorsement by the UNMC or
ACPE of any commercial products affiliated with this activity.
LEARNING OBJECTIVES
After completing this activity, the reader should be better able to:
• Summarize the initial findings of the Prostate Cancer Prevention Trial.
• Explain how finasteride may affect prostate cancer detection by prostate-specific antigen testing or digital rectal examination.
• Discuss how the use of a risk calculator may be helpful for patients and their physicians when evaluating prostate cancer risk and making decisions about prevention.

Initial PCPT findings
We first studied finasteride as a possible protective agent because it
blocks conversion of testosterone to the more potent androgen dihydrotestosterone involved in prostate cancer development. The large
(N = 18,882) National Cancer Institute–funded PCPT followed lowrisk men >55 years of age treated with placebo or finasteride (5 mg
daily) for 7 years to determine the drug’s effect on prostate cancer
detection.2 Men underwent annual PSA testing and DRE. Those with
abnormal DRE or annual PSA >4 ng/mL, adjusted for finasteride’s
effect, were referred for biopsy. This analysis revealed that:
• Finasteride reduced the risk of prostate cancer detection by 24.8%
overall (detection rates, 18.4% in the finasteride group vs 24.4%
in the placebo group, 95% confidence interval [CI], 18.6%30.6%, P <.001).
• Finasteride was associated with a higher risk of detecting highgrade malignancy. Gleason grade >7 tumors were identified in
6.4% of men in the finasteride group compared with 5.1% of men
in the placebo group, for a 27% higher risk (95% CI, 1.07-1.50,
P = .005).

Ian M. Thompson, MD, states that he is a consultant for
Veridex and Mission.
ACCREDITATION
The University of Nebraska Medical Center,
Center for Continuing Education is accredited
by the Accreditation Council for Pharmacy
Education as a provider of continuing pharmacy education. The ACPE provider number is 447-000-08-423H04-P. To receive the 1 contact hour of continuing education
credit, pharmacists should complete the activity requirements and evaluation at the conclusion of the activity.
Approval is valid from the initial release date of December 1,
2008. The expiration date is November 30, 2009. A statement
of credit will be available for printing online upon completion
of the post-test with a score of 70% or better and the evaluation instrument.

Continuing Education
Program #CIK9976 • RELEASE DATE: December 1, 2008 • EXPIRATION DATE: November 30, 2009
Because of this apparently elevated rate of aggressive
disease, finasteride did not enter common use as a
chemopreventive agent.

Continued investigation
The impact of finasteride on prostate gland size and
PSA levels was known before the PCPT. Therefore,
before ruling out finasteride as an effective chemopreventive agent, the study team undertook a series of
analyses to investigate finasteride’s effect on detection
of prostate cancer and high-grade disease. To determine
whether finasteride improved cancer screening, we
compared the predictive value of a positive DRE and/or
PSA levels between the placebo and finasteride arms
with biopsy findings. To determine whether finasteride
improved biopsy sensitivity to detect high-grade disease, we compared biopsy findings with radical prostatectomy samples. These studies revealed that:
• Finasteride significantly increased the sensitivity of
PSA testing for detecting prostate cancer (P
<.001) and high-grade (Gleason grade >7) disease
(P = .003).5
• Finasteride significantly increased the sensitivity of
DRE for detecting prostate cancer (P = .015).6
• Finasteride significantly increased the sensitivi-

ty of biopsy for detect- Figure. Prostate Cancer Detection Rates
ing high-grade malignancies, based on
comparison of Gleason
score at biopsy and
prostatectomy. Biopsy
detected 69.7% of
Gleason grade >7 malignancies that were
identified at prostatectomy in the finasteride group versus
50.5% of such cancers
in the placebo group
(P = .01).4
We proposed that the
increased sensitivity for
high-grade cancers most
likely resulted from the
reduction of median
prostate gland volume
seen with finasteride (25.1
cm3 finasteride vs 34.4 cm3
with placebo; P <.001).1,4
We also suggested that

he Prostate Cancer Prevention Trial randomized 18,882 men to receive finasteride, a
selective inhibitor of type 2 five-alpha
reductase or placebo to be followed annually for up
to 7 years for prostate cancer. The study, which
closed in 2003, showed that finasteride reduced the
risk of prostate cancer by at least 25%.1 Based on
study data, a calculator for the risk of prostate cancer and high-grade cancer (Gleason score >7) was
developed.2 Presented here are five cases from the
placebo arm that illustrate the diversity of prostate
cancer risk and the use of the risk calculator. The
calculator is intended to help inform the decision
process for patients and their physicians on the risk
of prostate cancer and the possible benefit of finasteride use for prevention of prostate cancer.
Case 1 is a white man, 62 years old at study
entry, with no family history of prostate cancer.
During his 7 years of follow-up in the study, he had
no clinical indications for biopsy of the prostate. At
his 7-year and final annual study visit, results of his
digital rectal examination (DRE) were normal, and
his prostate-specific antigen (PSA) level was 1.1
ng/mL. His end-of-study biopsy found no cancer.
According to the risk calculator, this patient has a
15% chance of prostate cancer and a 2% chance of
high-grade prostate cancer.
Case 2 is a white man, 67 years old at study
entry, with no family history of prostate cancer.
During his 7 years of follow-up in the study, he had
no clinical indications for biopsy of the prostate.
At his final visit, his DRE results were normal, and
his PSA level was 2.5 ng/mL. Prostate cancer was
detected on biopsy with a Gleason score of 6, indicating low-grade disease. This man has a 27% and
6% chance of prostate cancer and high-grade can-

cer, respectively.
Case 3 is a white man, 68 years old at study
entry, with a family history of prostate cancer. At
his 2-year visit, his PSA level was 2.4 ng/mL, and
his DRE results were abnormal. Results of a biopsy
of the prostate were negative. At his 6-year visit, his
PSA level was elevated at 4.3 ng/mL, and he again
had abnormal DRE results. He underwent a second
biopsy, and prostate cancer was detected with a
Gleason score of 6, indicating low-grade disease.
This man has a 47% and 19% chance of prostate
cancer and high-grade cancer, respectively.
Case 4 is a white man, 60 years old at study
entry, with no family history of prostate cancer. At
his 7-year visit, his PSA level was 5 ng/mL, and his
DRE results were normal. Results on biopsy of the
prostate were negative. This man has a 39% and
11% chance of prostate cancer and high-grade cancer, respectively.
Case 5 is a black man, 72 years old at study
entry, with no family history of prostate cancer. At
his 1-year visit, his PSA level was 0.3 ng/mL, and
his DRE results were abnormal. Prostate cancer was
detected on biopsy with a Gleason score of 6, indicating low-grade disease. This man has a 13% and
3% chance of prostate cancer and high-grade cancer, respectively.

finasteride may have selectively inhibited low-grade
cancers, leaving high-grade tumors constituting a
greater proportion of the total cancers detected.4
Counterbalancing these factors, men in the placebo
group were more likely to undergo biopsy. This latter
finding would bias results toward greater cancer detection in the placebo group.1
We then conducted a series of analyses in an effort to
control for these detection biases. We also incorporated
3 months of data not included in the 2003 report.
These additional data were gathered from when the
data set was frozen after the trial was stopped, up to its
unblinding.1

Latest findings
Our team recently published the latest findings from
these analyses.1
• Increased sensitivity of PSA and DRE did not considerably affect initial findings that finasteride significantly reduced risk of prostate cancer detection. Increased likelihood of biopsy in the placebo
group also did not substantially change results.
• Specifically, after accounting for these biases, finasteride reduced the risk of prostate cancer detection
by 30% (detection rates: 14.7% in the finasteride
group vs 21.1% in the placebo group [Figure]; 95%
CI, .64–.76; P <.0001) and there was a now-nonsignificant increased risk of high-grade cancer
(14%, 95% CI, .96–1.35; P = .12).
• Last, we controlled for the heightened biopsy sensitivity for the high-risk malignancies seen with
finasteride. This analysis showed that finasteride
significantly reduced the rate of both high-grade
(Gleason >7) and low-grade (Gleason <6) prostate
cancer, by an estimated 27% (95% CI, .56–.96;
P = .02) and 34% (95% CI, .55–.80; P <.0001),
respectively. We corrected for the increased biopsy
sensitivity to high-grade cancer seen with finasteride by attempting to estimate the rate of highgrade prostate cancer that would have been identified if all men with biopsy-detected malignancies
had undergone prostatectomy. About 25.5% of
study subjects with biopsy-detected malignancies
had their prostate removed and had prostatectomy
samples and biopsy grade information available for
analysis.4
Continued on page 23

Recommendations
• Whether healthy men should take finasteride for
prostate cancer prevention depends on many factors. These include the risk of prostate cancer, significance of the cancers that can be prevented, and
finasteride’s risk/benefit profile.
• Prostate cancer is common. Primarily because of
frequent screening, the estimated lifetime risk for
men in the United States is one in seven.1
• Identification of even low-grade cancer often
prompts men to seek treatment. Treatment has its
own costs and side effects; it also exacts an emotional toll on patients and their families.
• Finasteride significantly reduced the risk of both
low- and high-grade cancers. It decreases urinary

symptoms and complications of prostatic hypertrophy. We identified no evidence that finasteride
increased the risk of high-grade prostate cancer.
• Finasteride’s side effects include reduced sexual
function.
• Evidence supports offering finasteride to men at
risk for prostate cancer.
• Studies are needed to determine the optimal duration of therapy to prevent prostate cancer while
minimizing risk of side effects.3

he Prostate Cancer Prevention Trial
(PCPT) was the largest prostate cancer
prevention trial ever completed.1 The
positive results were tainted by the increased
incidence of high-grade tumors found in the
finasteride arm, thus muting the enthusiasm of
the medical community to use finasteride as a
preventive agent.
The current reanalysis of the PCPT data presented in the Redman article is one of many
attempts to evaluate the PCPT results to determine the real role of finasteride as a preventive
agent for prostate cancer. Redman and colleagues used advanced statistical modeling to
determine whether finasteride is truly increasing the risk of high-grade tumors or if there are
other factors that are lending bias to the interpretation of the data. The authors thoroughly
discuss the difference between the original data
and their findings and conclude that finasteride
does not increase the risk of high-grade prostate
cancer after 7 years of therapy.
The PCPT investigators suggest that finasteride increases the sensitivity of prostate-specific antigen (PSA) and digital rectal examination (DRE) for detecting prostate cancer.2,3
Finasteride decreases the prostate gland volume, therefore if there was tumor present, it
would be easier to detect by DRE or biopsy.
Finasteride decreases PSA levels to a greater
extent in the setting of benign prostatic hyperplasia, thus those men receiving finasteride
with persistently elevated PSA levels are more
likely to have prostate cancer, and the risk of
high-grade disease increases proportionally
with higher PSA levels. When the PCPT data

November/December 2008

were adjusted for prostate gland size, the biopsy
results showed there was no increase in highgrade tumors in the finasteride group.2
The amount of data that has been released
which contradicts the original conclusion of the
2003 PCPT data certainly has offered some clarification of the risks and benefits of finasteride
for prostate cancer prevention. Patients and
providers should feel comfortable that finasteride in the preventive setting is not selecting
out for high-grade tumors.

Patients and providers should
feel comfortable that finasteride in the preventive setting is not selecting out for
high-grade tumors.

and decreased over the 7 years of treatment.4
Patients in the PCPT received finasteride 5 mg
orally every day for up to 7 years of therapy.
Additional studies are required to determine the
minimally effective duration of therapy to
decrease potential adverse effects.
Thompson and colleagues developed a risk
calculator taking into account variables such as
PSA, DRE, age, race, family history, and history of
a prior negative biopsy.5 The calculator predicts
a patient’s risk for developing prostate cancer
and risk of high-grade disease. Use of these
results in combination with consideration of the
risks and potential benefits of finasteride therapy should be part of the counseling session with
all men older than 55 years of age. This can
assist the patient in determining the best course
of action based on the potential aggressiveness
of his disease and potentially decrease unnecessary systemic therapy in patients with low-risk
disease.
References

So what is the final recommendation for the
use of finasteride in prostate cancer prevention?
The American Urological Association and the
American Society of Clinical Oncology have yet
to make formal recommendations on the subject. The most common side effects reported in
the PCPT finasteride group were sexual dysfunction (reduced ejaculate volume, erectile dysfunction, and decreased libido) and gynecomastia. Older age predicts increased sexual
dysfunction with finasteride. The increase in
adverse effects in the finasteride arm was small

Finasteride and Prostate Cancer Prevention: The Latest Chapter
A Nurse’s Perspective
BY GARY SHELTON, MSN, ARNP, AOCN
New York University Cancer Institute, New York

O

ncology nurses tackle new knowledge
and balance it against old behavior.
Advanced practice nurses embrace this
role, allowing them a framework to promote
change that influences practice and ultimately
improves outcomes. We welcome research like
fresh air, hoping that findings will lead to evidence-based care that healthcare providers will
accept and promote. Prevention of cancer is of
primary interest.
A fresh look at the maturing data from the
Prostate Cancer Prevention Trial, in which men
took finasteride 5 mg daily for 7 years, reveals
interesting bias-adjusted data.1 It is now clearer that finasteride not only reduces the incidence of prostate cancer (chemoprevention),
but also allows for more accurate grading of the
disease when found through screening/early
detection. With better understanding of the
mechanism of action of finasteride (ie, shrinking the prostate gland and blocking the conversion of testosterone to dihydrotestosterone),
we see how finasteride increases the sensitivity of prostate-specific antigen testing and digital rectal examination for detecting prostate.
Men with benign prostatic hyperplasia take
finasteride as indicated to shrink the prostate
gland, thereby lessening urinary obstructive
symptoms. For many of these men, this benefit
outweighs the sexual side effect of erectile dysfunction. Men without urinary obstructive
symptoms may not see themselves as being at
risk for prostate cancer, and they may not be
ready to hear about medical interventions to
prevent the disease. Men without known
health problems may not actively be seen in
clinics or seek healthcare interventions.
As with all attempts at prevention of disease,
the proposed intervention must be seen as
beneficial and with acceptable side effects. In
the case of prostate cancer, there are a number

of questions to consider: Do men see themselves at risk of prostate cancer? Would they
consider an intervention to prevent cancer as
necessary? Are they aware of these new data?
How do we introduce the topic? Are men coming to our offices or are we reaching out to
them? An asymptomatic population may not
be aware of their risk of prostate cancer. All
men deserve the option of an intervention that
may either prevent disease or allow for easier
detection.
Nurses must be knowledgeable about
prostate cancer and comfortable about discussing it with their patients. They should discuss both the overall and relative risk for
prostate cancer and outline what is known
about the disease and its prevention. All men
deserve to be informed of ways to improve
their quality of life, especially through diet and
lifestyle changes.

All men deserve to be

Treatment with finasteride may also allow for
more accurate staging when cancer is detected,
making it possible to treat more aggressive disease earlier.
When men understand the risk/benefit ratio
of an intervention, they are more likely to consider the option. Being up front and candid
about side effects allows for discussion of possible treatments and approaches to dealing
with side effects. Referral to specialists may be
necessary at times.
Although finasteride cannot currently be
promoted for prostate cancer prevention, it is
our role and duty to make our patients aware of
recent research and their treatment options.
Cancer prevention interventions are routinely
discussed in all contact moments. Oncology
nurses should be up-to-date on research findings and offer education to peers and populations at risk to facilitate decision making and
patient advocacy.

informed of ways to improve
their quality of life, especially
through diet and lifestyle
changes.
Finasteride is not currently approved for
prostate cancer prevention and may not be
available to all men; however, evidence supports offering finasteride to men at risk for
prostate cancer. The incidence of prostate cancer is high, perhaps due in part to overscreening. By implementing chemoprevention with
finasteride, we may be able to stave off the
development of prostate cancer in some men.

To receive complimentary
CE credit:
1. Log on to
www.theoncologypharmacist.com.
2. Click on UNMC logo on homepage.
3. Register to participate.
4. Enter program number #CIK9976.

Reach us online at
www.theoncologypharmacist.com

24

G REEN H ILL H EALTHCARE C OMMUNICATIONS

• View current and past issues

• Access CE activities

• Register to receive your free
subscription

• Obtain author guidelines

November/December 2008

Using Upfront Contracts to Cure
Mutual Mystification

H

ave you ever thought that your
communication with people was
crystal clear and then find that
the other person didn’t get it? Typically
we think, “How could they not understand? They just don’t listen.” But maybe
your communication wasn’t as clear as
you thought it was. When two or more
people engage in communication but the
end result is neither person clearly understands what the other expressed, we call
that mutual mystification. If this is happening on a regular basis, a system of
agreement might help. We call it an upfront contract.
People communicate through different
methods. Upfront contracts are the mutually agreed upon expectations between
individuals, established before moving
forward in any endeavor. In any professional setting, whether it is business or the
practice of medicine, when you set an
upfront contract with a prospect or
patient, both of you have agreed on what
you want to accomplish and what will
happen next, provided a specific set of
events occurs. The mechanics are more
involved, but the concept is that simple.
An upfront contract in a typical discussion might set the parameters for what will
be discussed, what information will be provided by both the nurse and the patient,
and what the outcome of the action might
be at the end of the discussion.

The

Oncology
Nurse

The Official Newspaper
of Record for
the Hem/Onc Nurse

ic set of events occurs.
Upfront contracts often ease anxiety
that patients have due to the unknown.
Think of a child going the dentist. In the
old days, the dentist would command the
child to get in the chair and keep his
mouth open while the dentist poked,
picked, and shoveled power tools into his
mouth. Today, the dentist knows a little
more about upfront contracts and makes
the child feel more comfortable. The dentist may explain that he will only be in the
chair for 20 minutes and that he is only
inspecting and cleaning the child’s teeth.
He may also explain that none of the
tools he will use will hurt and may even
ask the child if he would like to watch a
cartoon. Now, the child may still feel a little stress, but it’s much easier than the initial situation.
November/December 2008

Pharmacist

™

SAGAR LONIAL, MD

Center of Excellence Media, along with Editor-in-Chief
Sagar Lonial, MD, of Emory University, will proudly offer the
multidisciplinary cancer team at your center a series of
newsletters focusing on the challenges in treating patients
with multiple myeloma.

The Sandler Sales Institute is an international sales and management training/consulting firm established in 1967. For more
information, in New Jersey call 732-764-0200 or visit their
website at PerformanceSellingLLC.com.

PROFESSIONAL DEVELOPMENT

By Jim

contract, you
are establishing
the ground rules
for a working
relationship beBarnoski
tween yourself
and others. The
contract describes which behaviors are expected to achieve those aspects of
the goal for which they will be responsible. For a computer
analyst, the goal could be a component of a software package; for a salesperson, the goal might be expressed as a sales
quota; for a nurse, the goal could be a higher level of satisfaction for the patients.
By discussing mutual expectations, you establish what is
expected of the others and what you need to provide. This
may be stated explicitly. For instance, the employee may

need training to achieve a particular outcome. Or, specific
coaching may be necessary to keep an employee on behaviors to achieve an outcome. Certain supervisory checkpoints
may be described and then established to maintain the flow
and pace of work.
Upfront contracts require work. First, there is the front-end
learning curve—gaining an understanding about how to set
upfront contracts. Second, there is the effort involved in actually setting the contract with the other person, a step most
people are not currently doing. Third, there is the continual
process of improving how you set contracts with others.
Contracts make your life easier, but they do require more
effort—an investment in time and energy that pays back
many times over.

Multidisciplinary Cancer Care newsletters provide a forum for sharing expert interdisciplinary treatment perspectives on patient care with the ultimate goal
of promoting ongoing professional education to physicians, nurses, and pharmacists in the hematology/oncology community.
Pharmacists

Target Audience
This educational publication is designed for physicians, nurses, and pharmacists who wish to
enhance their knowledge concerning the management of patients with multiple myeloma and
renal dysfunction.

Learning Objectives
At the completion of this educational activity, you should be able to:
• Describe the prevalence of renal insufficiency among patients with multiple myeloma (MM)
• Recognize the special challenges in pharmacologic treatment of the many patients with MM
who also have renal insufficiency, especially those requiring dialysis
• Discuss the results of studies showing treatments that are active and safe in MM patients with
renal impairment, including those with advanced renal failure requiring dialysis

Accreditation
Physicians
This activity has been planned and implemented in accordance with the Essential Areas and
Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the
joint sponsorship of CME Consultants and Center of Excellence Media. CME Consultants is
accredited by the ACCME to provide continuing medical education for physicians.
CME Consultants designates this educational activity for a maximum of 1.0 AMA PRA Category
1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

CME Consultants is accredited by the Accreditation Council for Pharmacy Education
as a provider of continuing pharmacy education.
This activity has been designated for 1 contact hour (0.100 CEU). In order to receive credit, all
participants must complete an evaluation, request for credit form, and a posttest. Statements of
Credit will be mailed to participants within six weeks. ACPE #309-999-08-012-H01-P
Initial Release Date: 05/07/08. Planned Expiration Date: 05/07/09.
Nurses
CME Consultants is accredited as a provider of continuing nursing education by the
American Nurses Credentialing Center’s Commission on Accreditation.
CME Consultants designates this program for 1 contact hour. Participants should claim only
those contact hours actually spent in the educational activity.
In order to receive credit for this program, each participant must complete the evaluation form,
posttest, and certificate request form. Certificates will be mailed to program participants in
approximately four to six weeks after receipt of the completed evaluation form, posttest, and certificate request form.

CO Center of Excellence Media, LLC
E
™

™

Your Innovative Partners in Continuing Education

Supported by an educational grant from Millennium Pharmaceuticals, Inc.

G REEN H ILL H EALTHCARE C OMMUNICATIONS

25

ADVANCED MELANOMA

abundance of molecular studies designed to clarify the role of this and
other pathways in melanomagenesis.
type of cancer in persons aged 20 to 30
Bcl-2, a protein overexpressed in
years and the primary cause of cancer about 80% of melanomas, inhibits
death in women aged 25 to 30 years, apoptosis and is believed to contribute
said Poust at a symposium held during to chemotherapy resistance, Poust said.
the 2008 Hematology/Oncology Phar- Oblimersen is a Bcl-2 antisense commacy Association/International Society pound that selectively targets Bcl-2
of Oncology Pharmacy Practitioners RNA for degradation and decreases Bcljoint annual conference.
2 protein production.
The risk of malignant melanoma
Poust described the findings of a randeveloping in an American in the domized study of 771 patients with
United States is now 1 in 87, an increase advanced melanoma treated with dacarof nearly 2000% since the 1930s. The bazine alone or preceded by a 5-day
increasing incidence of malignant continuous intravenous infusion of
melanoma is actual (ie, not due to oblimersen (J Clin Oncol. 2006;24:4738increased surveillance or changes in 4745). The addition of oblimersen to
diagnostic criteria) and expected to con- dacarbazine yielded a trend toward
tinue for at least the next 10 to 20 years. improved median survival (9.0 vs 7.8
Current options for the management months; P = .077) and significant
of advanced melanoma include surgery, increases in median progression-free
radiation, combination antineoplastic survival (PFS; 2.6 vs 1.6 months; P
chemotherapy, and systemic therapy <.001), overall response (13.5% vs
with dacarbazine, temozolomide, or 7.5%; P = .007), and durable response
interleukin-2. “The overall impact of (7.3% vs 3.6%; P = .03).
these approaches is minimal, and the
RAF proteins are serine/threonine
current 5-year survival rate is only 6%,” kinases that regulate cell proliferation,
Poust said.
differentiation, and survival, Poust
explained. BRAF mutations
occur in about 70% of melaTargeted inhibition of BRAF noma cell lines, he noted,
and targeted inhibition of
may be a useful strategy for BRAF may be a useful strategy for the treatment of
and other tumors.
the treatment of melanomas melanomas
Sorafenib is an oral multikinase inhibitor that inand other tumors.
hibits RAF serine/threonine
kinases and receptor tyrosine kinases involved in
Recent discoveries have provided tumor growth and angiogenesis. Soraincreased understanding of the molecu- fenib has been approved in several counlar events leading to melanoma devel- tries worldwide for the treatment of
opment and progression and the basis renal cell carcinoma and has demonfor a new generation of molecular-tar- strated preclinical and clinical activity
geted therapies, Poust said (Table). In in several tumor types.
particular, the identification of prevaIn a randomized study described by
lent activating mutations of the BRAF Poust, 101 patients with advanced
kinase in melanomas has led to an melanoma received dacarbazine with
Continued from cover

SKIN CANCERS

Ipilimumab Helps Latestage Melanoma Patients

SKIN CANCERS

STOCKHOLM—Nearly half of patients with unresectable stage III or IV melanoma who are treated with
the investigational monoclonal antibody ipilimumab
remain alive after 1 year, researchers announced at the
33rd Congress of the European Society for Medical
Oncology.
The results are from three phase 2 studies involving
a total of 487 previously treated patients who received
four doses of 10 mg/kg ipilimumab every 3 weeks for 12
weeks. Patients received maintenance dosing with
ipilimumab every 12 weeks starting at week 24.
The studies showed a 47% to 51% 1-year survival
rate, which includes patients who had progressed
while receiving standard treatment or relapsed or
failed to respond to other experimental treatments or
were unable to tolerate currently approved therapies.
According to recent reports, the 1-year survival rate
for advanced metastatic melanoma patients who
receive approved therapies is approximately 25%.
Ruggero Ridolfi, MD, with the Istituto Scientifico
Romagnolo per lo Studio e la Cura del Tumori (IRST)
in Meldova, Italy, who presented the results from one
of the trials, said that the findings on both efficacy and
safety corroborate those reported in other phase 2 tri26

placebo or sorafenib (J Clin Oncol.
2008;26:2178-2185). Median PFS was
21.1 weeks in the sorafenib plus dacarbazine arm and 11.7 weeks in the placebo plus dacarbazine arm (P = .068).
There were statistically significant
improvements in PFS rates at 6 and 9
months and in time to progression
(TTP) in favor of sorafenib plus dacarbazine, but no differences in overall survival were observed between the groups.
The addition of sorafenib to paclitaxel and carboplatin provided no additional improvements in overall survival,
TTP, or response rate in a randomized

phase 3 study of 270 patients with
advanced melanoma, Poust pointed out
(J Clin Oncol. 2007:25:8510). Median
PFS was 17.4 weeks in the three-drug
group and 17.9 weeks in the two-drug
group (P = .492), he noted.
Cytotoxic T-lymphocyte antigen 4
(CTLA-4) is a CD28 family receptor
expressed primarily on CD4+ T cells,
Poust said. CTLA-4 plays a key role in
the maintenance of T-cell homeostasis,
and blockade of CTLA-4 sustains T-cell
activation and proliferation.
The monoclonal anti-CTLA-4 antibodies ipilimumab and tremelimumab
have shown promising activity and
manageable toxicities in early clinical
trials in patients with advanced melanoma, Poust noted. The toxicity profiles
of these agents involve inactivation of
normal immunosuppressive homeostatic mechanisms and manifest as inflammatory bowel symptoms, uveitis, dermatitis, arthritis, and other disorders.
Melanoma vaccines are designed to
stimulate the formation of antibodies to
antigens found on melanoma cells and
are produced individually using a
patient’s own tumor cells, Poust explained. Examples of types of melanoma
vaccines include polyvalent melanoma
vaccine, heat shock protein vaccines,
antigen-bound vaccines, and dendritic
cell vaccines.
“Polyvalent melanoma vaccine stimulates cytotoxic T-cell immune responses in the host, resulting in inhibition of
tumor cell proliferation and tumor cell
death,” Poust said.
The results of large clinical trials of
melanoma vaccines have been disappointing, Poust noted, and vaccine
therapy remains experimental in this
population. Future treatment of advanced melanoma may involve a multimodal approach including vaccines,
adjuvants, and other targeted molecular
therapies, he added.
—DSM

als involving ipilimumab.
The analysis showed grade 3 immune-related
adverse events, including rash, diarrhea, and hepatitis,
in 20% to 28% of patients and grade 4 events in 0% to
12% of patients. Adverse events were generally manageable and reversible within days or weeks with the
use of supportive care and systemic steroids using
established treatment guidelines in the majority of
patients.

all skin cancer deaths. According to the American
Cancer Society, about 62,000 new cases of melanoma
will be diagnosed in the United States this year, and
roughly 8000 patients will die of the disease.

Although melanoma accounts

Know?

for only about 4% of all skin
cancers, the disease is
responsible for 79% of all
skin cancer deaths.
Phase 3 trials presently under way are examining the
role of ipilimumab in tandem with dacarbazine in
patients with untreated, unresectable stage III or IV
metastatic melanoma as well as ipilimumab administered as adjuvant therapy in patients with high-risk
stage III disease.
Although melanoma accounts for only about 4% of
all skin cancers, the disease is responsible for 79% of

G REEN H ILL H EALTHCARE C OMMUNICATIONS

—Jill Stein

Did you

The incidence of many common cancers is falling, but the incidence of
melanoma continues to rise significantly, at a rate faster than that of any
of the seven most common cancers.
Approximately 62,480 melanomas
will be diagnosed this year.
Source: www.skincancer.org.
November/December 2008

Visit Booth #1127 at
ASHP MCM to take the pH test
and register to win a Wii

Strip away the claims

See for yourself what others
have already conﬁrmed
Other drug transfer devices claim to be closed, but they lack the independent, clinical evidence to prove it. They claim to offer affordability,
but their incompatibility with all drugs and vial sizes means you’ll pay more with inadequate coverage and drug waste. They claim familiar
ease of use, but their wet connections guarantee exposure, even with perfect user form.
Strip away the claims and see for yourself what others have already conﬁrmed. Ordinary lemon juice and litmus strips
(or sodium bicarbonate and urine dipsticks) are all you need to conduct a simple pH test to determine the leakproof integrity of today’s
available transfer devices. So take the test—and then demand the facts.

No leakage was observed after 10 manipulations with the PhaSeal System.
Visible leakage occurred outside of the ICU Medical System, the B. Braun OnGuard™ System and the Cardinal Health/Alaris System during all manipulations.

Backed by 14+ years of experience devoted solely to the development of our closed-system drug transfer device (CSTD) and supported by
more than 10 independent, peer-reviewed, published clinical studies, we can factually state that our product offers clinically-proven,
full spectrum protection. Can they?

Know You’re Safe With
Find more information and evidence-based research at www.PhaSeal.com or call 866-487-9250

FDA Approves New Patch to
Treat CINV
SEATTLE—The first and only patch to provide up to 5 consecutive days of control of nausea and vomiting for patients
receiving a moderately and/or highly nausea-inducing
chemotherapy has been approved and is now heading to
pharmacy shelves. The Granisetron Transdermal System
(Sancuso), which was approved by the US Food and Drug
Administration (FDA) in September 2008, is the only 5hydroxytryptamine 3 (5-HT3) patch approved for the prevention of chemotherapy-induced nausea and vomiting
(CINV). Granisetron is also available in oral and intravenous (IV) formulations.

setron is given orally or through IV,” said Rogers in an interview with The Oncology Pharmacist. “There is no comparison,
but we expect it to be similar or be less of a problem when it
comes to constipation. Does a steady flow of the drug from
the patch cause more constipation or less? We don’t know. It
might be peak effects that cause more of a problem, but we
don’t know that. We don’t expect it to be worse as far as more
side effects, but it may be less because there is a more steady
flow of the drug and no peaks and valleys that may cause
constipation.”
Use of the patch is contraindicated in patients with
known hypersensitivity to granisetron or to any of
We should have zero tolerance for CINV. the components of the patch. The makers of the
patch say granisetron may mask a progressive ileus
and/or gastric distention caused by the underlying
A patch that can be applied before
condition. In addition, patients should avoid direct
of the application site to natural or artifitreatment, releasing medication consis- exposure
cial sunlight by covering with clothing while wearing the patch and for 10 days after removing it.

tently into the bloodstream over a number of days, has the potential to impact

—John Schieszer

patient comfort and quality of life.

FDA REPORT

Granisetron is a selective 5-HT3 receptor antagonist with
little or no affinity for other serotonin receptors. Similar to
other 5-HT3 receptors, granisetron prevents serotonin from
binding to 5-HT3 receptors. By preventing activation of
these receptors, 5-HT3 antagonists interrupt one of the pathways that lead to vomiting. Studies have shown that by binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after chemotherapy.
“We should have zero tolerance for CINV. A patch that
can be applied before treatment, releasing medication consistently into the bloodstream over a number of days, has the
potential to impact patient comfort and quality of life,” said
Barbara Rogers, CRNP, MN, who is an adult hematologyoncology nurse practitioner at Fox Chase Cancer Center,
Philadelphia. She said that the approval of this patch should
lead to improved management of CINV because it adds a
new tool to clinicians’ armamentarium. She said it is imperative that oncology pharmacists are aware of the approval of
this patch.
Patches contain 34.3 mg of granisetron and release 3.1 mg
of the drug every 24 hours for 7 days. In adults, the patch is
applied up to a minimum of 24 hours before chemotherapy,
but may be applied up to a maximum of 48 hours before
chemotherapy. The patch should be removed a minimum of
24 hours after completion of chemotherapy.
The FDA approved the patch for the prevention of CINV
based on results of a multicenter, phase 3, randomized, double-blind, double-dummy, controlled study. The investigators
compared the efficacy, tolerability, and safety of the patch
with once-daily oral granisetron (2 mg) in 641 patients
receiving moderately or highly nausea-inducing multiday
chemotherapy. The trial met its primary end point of achieving complete control of CINV, working as well as oral
granisetron. Complete control was defined as no vomiting
and/or retching, no more than mild nausea, and no rescue
medication from first administration of the patch until 24
hours after the last day of chemotherapy.
In clinical trials, the patch was generally well-tolerated.
Adverse reactions considered drug-related by investigators
occurred in 8.7% of patients receiving the patch. Constipation was the most common drug-related adverse reaction. Application site reactions were reported but were mild
and did not lead to drug discontinuation. The incidence of
skin reactions was comparable to that with placebo.
“It is a drug we know and a route of administration that we
already have. Constipation is a common problem. So, the
constipation is nothing new that we don’t see when grani28

G REEN H ILL H EALTHCARE C OMMUNICATIONS

Casopitant Bolsters
Prevention of
Chemotherapy-related
Nausea and Vomiting
STOCKHOLM—The use of casopitant in combination
with standard care is superior to standard care alone for the
prevention of chemotherapy-induced nausea and vomiting
in patients receiving highly emetogenic chemotherapy
(HEC), according to phase 3 results released at the 33rd
Congress of the European Society for Medical Oncology.
Casopitant is a novel neurokinin-1 receptor antagonist.
Steven Grunberg, MD, an oncologist at the University of
Vermont in Burlington, and coworkers tested the use of a single oral dose or a 3-day intravenous (IV)/oral regimen of
casopitant plus standard care (ondansetron plus dexamethasone) in 810 cancer patients who were receiving HEC.
Overall, 99% of patients received cisplatin-based HEC regimens for up to six cycles.
Patients were randomized to a control arm, single oral dose
casopitant arm, or a 3-day IV/oral dosage casopitant arm and
continued on the same treatment arm throughout the study.
The primary study end point was the proportion of patients
achieving a complete response (CR), defined as no vomiting/retching and no use of rescue medications during the first
120 hours.
Results showed that patients who received the single oral
dose and 3-day IV/oral dosage casopitant regimens had statistically significant improvements in CR rates compared with
the control arm (86% and 80% vs 66%, respectively).
Significantly more patients in each casopitant arm achieved
CR versus patients in the control arms in both the acute
phase and the delayed phase. The benefits with casopitant
were maintained in the first four cycles of chemotherapy.
The study also found that significantly more patients who
received casopitant had no significant nausea, no nausea,
and no vomiting overall compared with the control group.
Both casopitant-based regimens were well tolerated with
minimal and manageable side effects. The most commonly
observed adverse events were those typically associated with
myelosuppressive cisplatin-based chemotherapy.

Recent FDA
Approvals
• Full Approval for Denileukin
Diftitox for CTCL
The US Food and Drug Administration (FDA) has approved
an efficacy supplemental biologics license application for
denileukin
diftitox
solution
(Ontak; Eisai) for intravenous
treatment of patients with persistent or recurrent cutaneous Tcell lymphoma (CTCL) whose
malignant cells express the CD25
component of the IL-2 receptor.
The FDA’s action marks the conversion of an accelerated approval indication to full approval
based on results of a phase 3 trial.

• New Indications for HPV
Vaccine
The FDA has approved the
human papillomavirus (HPV)
quadrivalent (types 6, 11, 16, and
18) vaccine, recombinant (Gardasil;
Merck) for prevention of vaginal
and vulvar cancer caused by HPV
types 16 and 18 in girls and
women 9 to 26 years of age. The
vaccine was originally approved
in 2006 for the prevention of cervical cancer, precancerous genital
lesions, and genital warts.

• Receives Third US Approval for
Pemetrexed
The FDA has granted approval
for use of pemetrexed for injection (Alimta; Lilly) in combination
with cisplatin as first-line treatment of locally advanced and
metastatic non–small-cell lung
cancer (NSCLC) in patients with
nonsquamous histology. This is
the third US approval for the drug,
which was approved in 2004 in
combination with cisplatin for
unresectable malignant pleural
mesothelioma and as a single
agent for second-line treatment
of locally advanced or metastatic
NSCLC after prior chemotherapy.

• Device Cleared to Assess
Lymphedema
ImpediMed has received FDA
510(k) clearance for the L-Dex
U400 bioimpedance spectroscopy
device to assist physicians and
other medical professionals in the
clinical assessment of unilateral
lymphedema of the arm in
women with breast cancer. The
device, which uses the characteristics of frequency-dependent
current flow to quantify changes
in extracellular fluid in the
patient’s limb, can be used preoperatively and postoperatively. It
provides an immediate result,
and accompanying software can
be used to track changes in the
patient’s L-Dex value over time.

—Jill Stein
November/December 2008

JANUARY 2009

DECEMBER 2008

6 - 9 SAN FRANCISCO, CA

10 - 14 SAN ANTONIO, TX 11 - 12 WASHINGTON, DC 15 - 17

50th Annual Meeting and
Exposition
American Society of Hematology
www.hematology.org

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan®
(rituximab) is indicated for the treatment of patients with: Relapsed or refractory,
low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously
untreated follicular, CD20-positive, B-cell NHL in combination with CVP
chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy;
Previously untreated diffuse large B-cell, CD20-positive NHL in combination with
CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND
PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal,
infusion reactions. Severe reactions typically occurred during the first infusion with
time to onset of 30–120 minutes. Rituxan-induced infusion reactions and
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,
ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate
patients with an antihistamine and acetaminophen prior to dosing. Institute
medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or
oxygen) for infusion reactions as needed. Depending on the severity of the
infusion reaction and the required interventions, consider resumption of the
infusion at a minimum 50% reduction in rate after symptoms have resolved.
Closely monitor the following patients: those with preexisting cardiac or
pulmonary conditions, those who experienced prior cardiopulmonary adverse
reactions, and those with high numbers of circulating malignant cells
(>25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse
Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume
followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or
hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal
TLS cases have occurred after administration of Rituxan. A high number of
circulating malignant cells (*25,000/mm3) or high tumor burden confers a greater
risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.
Correct electrolyte abnormalities, monitor renal function and fluid balance, and
administer supportive care, including dialysis as indicated. [See Boxed Warning.]
Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal
outcome, can occur in patients treated with Rituxan. These reactions include
paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,
vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these
reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue
Rituxan in patients who experience a severe mucocutaneous reaction. The safety
of readministration of Rituxan to patients with severe mucocutaneous reactions
has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive
Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML
and death can occur in Rituxan-treated patients with hematologic malignancies or
with autoimmune diseases for which Rituxan has not been approved. The majority
of patients with hematologic malignancies diagnosed with PML received Rituxan
in combination with chemotherapy or as part of a hematopoietic stem cell
transplant. The patients with autoimmune diseases had prior or concurrent
immunosuppressive therapy and were diagnosed with PML within 12 months of
their last infusion of Rituxan. Consider the diagnosis of PML in any patient
presenting with new-onset neurologic manifestations. Evaluation of PML includes,
but is not limited to, consultation with a neurologist, brain MRI, and lumbar
puncture. Discontinue Rituxan and consider discontinuation or reduction of any
concomitant chemotherapy or immunosuppressive therapy in patients who
develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV)
Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic
failure, and death can occur in patients with hematologic malignancies treated
with Rituxan. The median time to the diagnosis of hepatitis was approximately 4
months after the initiation of Rituxan and approximately one month after the last
dose. Screen patients at high risk of HBV infection before initiation of Rituxan.
Closely monitor carriers of hepatitis B for clinical and laboratory signs of active
HBV infection for several months following Rituxan therapy. Discontinue Rituxan
and any concomitant chemotherapy in patients who develop viral hepatitis, and
institute appropriate treatment including antiviral therapy. Insufficient data exist
regarding the safety of resuming Rituxan in patients who develop hepatitis
subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections
The following additional serious viral infections, either new, reactivated, or
exacerbated, have been identified in clinical studies or postmarketing reports. The
majority of patients received Rituxan in combination with chemotherapy or as part
of a hematopoietic stem cell transplant. These viral infections included
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West
Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as
one year following discontinuation of Rituxan and have resulted in death. [See
Adverse Reactions.] Cardiovascular Discontinue infusions for serious or lifethreatening cardiac arrhythmias. Perform cardiac monitoring during and after all
infusions of Rituxan for patients who develop clinically significant arrhythmias or
who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal
Severe, including fatal, renal toxicity can occur after Rituxan administration in
patients with hematologic malignancies. Renal toxicity has occurred in patients
with high numbers of circulating malignant cells (>25,000/mm3) or high tumor
burden who experience tumor lysis syndrome and in patients with NHL
administered concomitant cisplatin therapy during clinical trials. The combination
of cisplatin and Rituxan is not an approved treatment regimen. Use extreme
caution if this non-approved combination is used in clinical trials and monitor
closely for signs of renal failure. Consider discontinuation of Rituxan for patients
with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction and perforation, in some cases leading to
death, can occur in patients receiving Rituxan in combination with chemotherapy.
In postmarketing reports, the mean time to documented gastrointestinal

perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough
diagnostic evaluation and institute appropriate treatment for complaints of
abdominal pain, especially early in the course of Rituxan therapy. [See Adverse
Reactions.] Immunization The safety of immunization with live viral vaccines
following Rituxan therapy has not been studied and vaccination with live virus
vaccines is not recommended. For NHL patients, the benefits of primary or
booster vaccinations should be weighted against the risks of delay in initiation of
Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood
counts (CBC) and platelet counts at regular intervals during Rituxan therapy and
more frequently in patients who develop cytopenias [see Adverse Reactions]. The
duration of cytopenias caused by Rituxan can extend months beyond the
treatment period. ADVERSE REACTIONS The most common adverse reactions of
Rituxan (incidence *25%) observed in patients with NHL are infusion reactions,
fever, chills, infection, asthenia, and lymphopenia. The most important serious
adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,
mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML,
other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction
and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reflect the rates observed
in practice. The data described below reflect exposure to Rituxan in 1606
patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan
was studied in both single-agent and active-controlled trials (n = 356 and n =
1250). These data were obtained in adults with low-grade, follicular, or DLBCL
NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,
given as a single agent weekly for up to 8 doses, in combination with
chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.
Infusion Reactions In the majority of patients with NHL, infusion reactions
consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,
headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or
hypertension occurred during the first Rituxan infusion. Infusion reactions typically
occurred within 30 to 120 minutes of beginning the first infusion and resolved
with slowing or interruption of the Rituxan infusion and with supportive care
(diphenhydramine, acetaminophen, and intravenous saline). The incidence of
infusion reactions was highest during the first infusion (77%) and decreased with
each subsequent infusion. [See Boxed Warning, Warnings and Precautions.]
Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,
occurred in less than 5% of patients with NHL in the single-arm studies. The
overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%,
and fungal 1%). [See Warnings and Precautions.] In randomized, controlled
studies where Rituxan was administered following chemotherapy for the
treatment of follicular or low-grade NHL, the rate of infection was higher among
patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral
infections occurred more frequently in those who received Rituxan. Cytopenias
and hypogammaglobulinemia In patients with NHL receiving rituximab
monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of
patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),
anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia
was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116
days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and
two occurrences of hemolytic anemia following Rituxan therapy occurred during
the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell
depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG
serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse
reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of
Rituxan administered as a single agent. Most patients received Rituxan 375
mg/m2 weekly for 4 doses.
Table 1
Incidence of Adverse Events in *5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b